Cannabinoid and opioid drugs produce marked changes in body temperature. Recent findings have extended our knowledge about the thermoregulatory effects of cannabinoids and opioids, particularly as related to delta opioid receptors, endogenous systems, and transient receptor potential (TRP) channels. Although delta opioid receptors were originally thought to play only a minor role in thermoregulation compared to mu and kappa opioid receptors, their activation has been shown to produce hypothermia in multiple species. Endogenous opioids and cannabinoids also regulate body temperature. Mu and kappa opioid receptors are thought to be in tonic balance, with mu and kappa receptor activation producing hyperthermia and hypothermia, respectively. Endocannabinoids participate in the febrile response, but more studies are needed to determine if a cannabinoid CB1 receptor tone exerts control over basal body temperature. A particularly intense research focus is TRP channels, where TRPV1 channel activation produces hypothermia whereas TRPA1 and TRPM8 channel activation causes hyperthermia. The marked hyperthermia produced by TRPV1 channel antagonists suggests these warm channels tonically control body temperature. A better understanding of the roles of cannabinoid, opioid, and TRP systems in thermoregulation may have broad clinical implications and provide insights into interactions among neurotransmitter systems involved in thermoregulation.

Keywords: Cannabinoid, Opioid, TRPV1, Sigma, Thermoregulation, Body Temperature, TRPM8, TRP81, Ananandamide

3.1. Kappa opioid receptors and body temperature

Three types of opioid receptors – delta, mu, and kappa opioid – mediate the thermoregulatory effects of opioids. Kappa opioid receptor activation produces hypothermia in rats and mice (Geller et al., 1982, 1983; Benamar et al., 2002;Spencer et al., 1988). Much of the early work investigating a role for kappa opioid receptors in thermoregulation was directed at the thermoregulatory effects of morphine. The administration of morphine to rats at doses of 4 to 15 mg/kg morphine produces robust hyperthermia, but progressively higher doses induce hypothermia (Geller et al., 1983). Experiments using selective opioid receptor agonists and antagonists reveal that mu opioid receptor activation is responsible for the hyperthermic response to morphine whereas kappa opioid receptor activation mediates the hypothermic effect of morphine (Spencer et al., 1988; Handler et al., 1992; Adler and Geller, 1993; Adler, 1983; Geller et al., 1986; Spencer et al., 1988; Adler et al., 1988; Handler et al., 1992, 1994; Chen et al., 1995, 1996, 2005; Wang et al., 2008; Nemmani et al., 2001; Xin et al., 1997). The hypothermic effects of kappa opioid receptor agonists have been thoroughly reviewed (Adler and Geller, 1993), but little is known about the mechanism of hypothermic action and the neurotransmitter systems involved. Recent studies suggest the hypothermic effect of kappa opioid receptor agonists is modulated by a number of transmitter and second messenger systems, including but not limited to glutamate, nitric oxide, calcium channels, serotonin (5-HT), nociceptin/orphanin FQ, pertussis toxin, cholera toxin, biogenic amines, neurotensin, and G-protein-gated potassium (GIRK) channels (e.g., loperamide, baclofen, oxotremorine, and ethanol are examples of drugs that produce hypothermia that is dependent on the GIRK2 gene) (Rawls et al., 2007a; Shukla et al., 1995; Nemmani et al., 2001; Handler et al., 1995;Gullapalli et al., 2002; Gullapalli and Ramarao, 2002a, b; Benamar et al., 2002;Salmi et al., 2003; Costa et al., 2005). The hypothermia induced by U50,488H is enhanced by the selective serotonin reuptake inhibitor (SSRI) fluoxetine, thus demonstrating that a 5-HT reuptake block, and subsequent elevation in extracellular 5-HT levels, increases kappa opioid receptor-evoked hypothermia (Nemmani et al., 2001). U50,488H-induced hypothermia is also augmented by chlorpromazine, indicating that kappa-opioid-receptor-mediated hypothermia is sensitive to the actions of biogenic amines (Adler and Geller, 1987). Similarly, U50,488H in combination with neurotensin produced a dose-dependent and additive hypothermia (Handler et al., 1995).

The hypothermic response to kappa opioid receptor activation is markedly influenced by nitric oxide, a diverse second messenger produced in both the peripheral and central nervous systems (Bredt and Synder, 1992; Breder and Saper, 1996; Lopez-Figueroa et al., 1998; Moncada et al., 1991; Lowenstein et al., 1992). Thermoregulation and fever, as well as body temperature changes produced by drug exposure, are sensitive to the level of nitric oxide production. Studies have produced inconsistent results, however, with some reporting that nitric oxide displays antipyretic properties and participates in the production of hypothermia (Moncada et al., 1991; Gourine, 1995; Branco et al., 1997; Steineret al., 1998; Almeida and Branco, 2001) whereas others suggest nitric oxide formation contributes to fever generation (Lin and Lin, 1996; Scammell et al., 1996; Roth et al., 1998; Benamar et al., 2000). With regard to kappa opioid hypothermia in rats, pharmacological evidence indicates peripheral and central nitric oxide production may be required (Benamar et al., 2002). The nonspecific nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg, s.c. or 1 mg/kg, i.c.v.) prevents the hypothermic effect produced by U50,488H (10 mg/kg, s.c.) (Benamar et al., 2002). The efficacy of i.c.v. L-NAME indicates the hypothermic response is dependent on nitric oxide production in the brain, a finding that is in agreement with prior work showing that central nitric oxide production is necessary for the hypothermic actions of insulin and arginine vasopressin (Almeida and Branco, 2001; Steiner et al., 1998). It should be noted that the sites of action of L-NAME are distributed ubiquitously throughout the body, including the brown adipose tissue, where they mediate heat production, and the vascular smooth muscle, where they mediate heat conservation (Taylor and Bishop, 1993; Nagashima et al., 1994). Thus, it is also possible that peripheral nitric oxide production participates in the hypothermia caused by kappa opioid receptor activation.

Many researchers in the field are now directing efforts toward identifying molecular targets which mediate the hypothermic response with the ultimate goal of determining whether a final common pathway is responsible for the production of hypothermia (Costa et al., 2005). One target of great interest is the G-protein-gated potassium (GIRK) channel. These channels are modulated by a variety of G-protein-coupled neurotransmitter receptors (GPCRs), including serotonergic (5-HT1A), GABAergic (GABAB), muscarinic (M2), adenosine (A1), opioid, adrenergic, and dopaminergic (D2) receptors (Yamada et al., 1998). Their primary functions are regulation of cellular excitability and action potential duration as well as maintenance of resting membrane potential. Neuronal cells predominantly express GIRK1, GIRK2, and GIRK3 but also express GIRK4 to a lesser extent (Wickman et al., 2000). GIRK channel activation typically decreases neuronal firing rate. Pharmacological activation of the same GPCRs that are known to positively modulate GIRK channels also produces hypothermia in rodents (Jackson and Nutt, 1991; Meller et al., 1992;Anderson et al., 1994; Malberg and Seiden, 1997; Eltayb et al., 2001; Baker and Meert, 2002). Novel experiments conducted in GIRK2 null mutant mice indicate activation of GIRK2-containing potassium channels plays a significant role in hypothermia induced by the activation of serotonergic (5-HT1A), GABAergic (GABAB), muscarinic (M2), adenosine (A1), and mu, delta, and kappa opioid receptors (Costa et al., 2005). In light of these results and documented evidence that GIRKs are final common effectors for many central neurotransmitter systems, GIRK2-containing channels may act as molecular hubs to control the hypothermic response to a variety of pharmacologically and structurally distinct drugs. In addition to GIRK channels, calcium channels are also thought to play a key role in kappa opioid hypothermia, as U-50,488H-indued hypothermia is mediated through PTX-sensitive transducer G-proteins (G(i/o)) coupled to L-type Ca2+ channels (Gullapalli and Ramarao, 2002).

The development of tolerance to kappa opioid hypothermia is a particularly interesting phenomenon which is related directly to excessive glutamate signaling. U50,488H, when administered repeatedly to rodents, loses its hypothermic efficacy (Von Voigtlander and Lewis, 1982; Milanés et al., 1991;Rawls et al., 2008a). The mechanism of tolerance is not entirely clear, but increased glutamate signaling plays a critical role (Trujillo and Akil, 1991;Kolesnikov et al., 1993; Aghajanian et al., 1994). The extent to which changes in glutamate activity contribute to opioid tolerance is dependent on the class of opioid agonist and biological endpoint which is investigated. For example, development and expression of the analgesic tolerance produced by repeated morphine administration is largely due to increased NMDA receptor activation (Marek et al., 1991; Trujillo and Akil, 1991; Pasternak et al., 1995; Popik and Skolnick, 1996). A role for NMDA receptors in tolerance to the analgesic effect of kappa opioid receptor agonists has not been consistently demonstrated, with some studies demonstrating that NMDA antagonists block tolerance and others reporting no effect (Kolesnikov et al., 1993; Bhargava and Thorat, 1994;Bhargava and Matwyshyn, 1993; Bhargava, 1995; Lutfy et al., 1999; Elliott et al., 1994). Interestingly, NMDA receptor antagonism does not alter the hypothermic tolerance to NMDA receptors (Bhargava, 1995; Bhargava and Matwyshyn, 1993;Bhargava and Thorat, 1997).

Another element of the glutamate system, glutamate transporter subtype 1 (GLT-1), does impact kappa opioid hypothermic tolerance. Recent experiments demonstrate that GLT-1 transporter activation prevents the hypothermic tolerance normally produced by U50, 488H (Rawls et al., 2008b). In those experiments, a single injection of U-50,488H (20 mg/kg, s.c.) induced significant hypothermia in rats (Rawls et al., 2008). Tolerance to the hypothermic effect of U50,488H was induced by injecting rats with U50,488H (20 mg/kg) twice daily for 7 days. When rats treated repeatedly with U50,588H were also exposed to ceftriaxone (200 mg/kg, i.p.), a beta-lactam antibiotic and GLT-1 transporter activator, the acute hypothermic response to U50,488H was not affected but the development of tolerance to U50,488H-induced hypothermia was completely prevented. The injection of dl-threo-β-benzyloxyaspartic acid (TBOA) (0.2 µmol, i.c.v.), a non-transportable inhibitor of glutamate uptake, into the lateral ventricle completely blocks the ceftriaxone effect, indicating the mechanism of ceftriaxone action was increased cellular glutamate uptake. This finding identifies a functional interaction between morphine and beta-lactam antibiotics, one of the world’s most widely prescribed drug classes. Other studies have also demonstrated a functional interaction between the opioid system and beta-lactam antibiotics, which are the only practical pharmaceuticals known to enhance glutamate uptake through GLT-1 transporter activation (Rawls et al., 2007b, 2010a, b; Rothstein et al., 2005;Miller et al., 2008; Sari et al., 2009; Knackstedt et al., 2009; Lipski et al., 2007;Chu et al., 2007; but see Melzer et al., 2008). Increased cellular glutamate uptake would be expected to reduce extracellular glutamate and produce an overall reduction in glutamate transmission which is normally produced by repeated exposure to a kappa opioid agonist. Therefore, the explanation most consistent with the current literature is that development of hypothermic tolerance to U50,488H is highly dependent on an increase in glutamate transmission, and that GLT-1 transporter activation by a beta-lactam antibiotic helps to preserve the hypothermic efficacy of U50,488H by abolishing the glutamate-dependent component of tolerance.

3.2. Delta opioid receptors and body temperature

Early work suggested only a minor role for delta opioid receptors in thermoregulation, but recent studies using selective and more pharmaceutically-friendly non-peptide delta opioid agonists suggest a more significant role for these receptors (Broccardo and Imprato, 1992; Handler et al., 1992, 1994; Pohorecky et al., 1999; Baker and Meert, 2002; Salmi et al., 2003; Rawls et al., 2005a; Rawls and Cowan, 2006). Low doses of deltorphin-II, a delta2 agonist, injected centrally produce hypothermia whereas higher doses of the agonist produce a biphasic response of hypothermia followed by hyperthermia (Salmi et al., 2003). The hypothermic effect of deltorphin-II is antagonized by the delta opioid receptor antagonist naltrindole, thus indicating that delta opioid receptor activation was the mechanism of action of deltorphin-II.

Early studies attempting to link delta opioid receptors and thermoregulation relied exclusively on the use of peptidergic agonists, which had to be administered centrally to avoid inactivation by peripheral peptidase action. The latest studies rely more upon non-peptide delta opioid agonists. These compounds were developed commercially because of their improved side effect profile (i.e., less respiratory depression and constipation) relative to morphine and mu opioid agonists. Because non-peptide opioid agonists are also resistant to peripheral peptidase inactivation, they are produce quantifiable central effects following systemic administration. The non-peptide delta opioid agonist that has received the most attention is (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), a diphenylmethylpiperazine derivative. SNC-80 is highly selective for delta opioid receptors over mu and kappa opioid receptors, and several observations suggest that the pharmacological profile of SNC-80 differs from that of peptide agonists, such as DPDPE (delta1), DADLE (mu/delta), and deltorphin-II (delta2) (Bilskyet al., 1995; Broom et al., 2002; Calderon et al., 1994; Knapp et al., 1996). Although SNC-80 is 1000-fold less potent than deltorphin-II in stimulating locomotor activity in rats, the lower potency does not correlate with differences in brain penetration for SNC-80 and deltorphin-II or with the superior binding affinity and efficacy of SNC-80 at delta opioid receptors in rat brain homogenates (Fraser et al., 2000). In a series of elegant experiments, Baker and Meert (2002) used delta opioid receptor antagonists to characterize the hypothermic effects of SNC-80 in mice (Baker and Meert, 2002). Their work revealed that SNC-80 induced dose-dependent hypothermia that was blocked by naltrindole; decreased by low doses of naltriben, a delta2 antagonist; and not affected by BNTX, a delta1 antagonist. Work by our own laboratory confirmed the robust hypothermic effects of SNC-80 in rats and subsequently used the versatile non-peptide agonist to identify the receptor phenotype, delta1 or delta2, which mediated the hypothermia. Experiments indicated that the systemic administration of SNC-80 induced dose-dependent hypothermia that was rapid in onset and persistent (Rawls et al., 2005a). The most interesting finding was that the hypothermic effect of SNC-80 was completely blocked by pre-treatment with naltriben but not BNTX. The ineffectiveness of BNTX, coupled with the efficacy of naltriben, suggests SNC-80 activated delta2 opioid receptors to induce hypothermia. This work also revealed that SNC-80 acted in the brain to produce hypothermia because administration of naltriben into the ventricles completely blocked SNC-80-evoked hypothermia.

The specific brain site of action of SNC-80 is unknown. A likely candidate is the preoptic anterior hypothalamus (POAH), a major central site of thermoregulation (Boulant, 1981). Delta opioid receptor binding has been detected in the POAH but is sparse compared to kappa and mu opioid receptor labeling (Mansour et al., 1987; 1994). Central delta opioid receptors produce a significant hypothermic response in rats and mice upon activation. Experiments conducted in rats demonstrated that the hypothermic response to SNC-80 is not affected by pretreatment with the peripherally restricted opioid antagonist methlynaltrexone, thus indicating the hypothermic mechanism of action of SNC-80 is entirely independent of peripheral opioid receptor activation (Rawlset al., 2005a). A lack of involvement of peripheral opioid receptors in rats contrasts with results in mice, where SNC-80 induces hypothermia which is partially dependent on peripheral opioid receptor activation (Baker and Meert, 2002). In addition, loperamide, a peripherally restricted opioid agonist, produces hypothermia in mice that is attenuated by both naltrindole and naltriben (Baker and Meert, 2002). Still another study indicates the peripherally restricted kappa opioid agonist (RS)-[3-[1-[[(3,4-Dichlorophenyl)acetyl]methylamino]-2- (1-pyrrolidinyl)ethyl]phenoxy]acetic acid hydrochloride (ICI 204448) (2.5, 5, and 10 mg/kg, s.c.) produces hypothermia in rats exposed to cold ambient temperatures (Rawls et al., 2005b). One surprising finding is that the direct injection of deltorphin-II into the POAH produces hyperthermia, instead of hypothermia (Benamar et al., 2004). This outcome underscores how the thermoregulatory effects of delta opioid agonists, akin to agonists at kappa and mu opioid receptors, vary widely with the administration route and indicates delta opioid agonists act at both hypothalamic and extra-hypothalamic delta2 receptors to produce changes in body temperature (Wallenstein, 1982).

A significant role for delta2 opioid receptors in thermoregulation has been demonstrated, but the impact of delta1 opioid receptors is less clear. Experiments conducted in rats reveal that pretreatment with BNTX does not affect the hypothermic response to SNC-80, thus indicating that delta1 opioid receptors are not a primary mediator of the hypothermia produced by SNC-80 in rats (Rawls et al., 2005a). BNTX also failed to reverse SNC-80-induced hypothermia in mice when it was tested in a different experimental design, one in which the delta1 opioid receptor antagonist was administered 15 min following SNC-80 administration (Baker and Meert, 2002). It should be noted, however, that a role for delta1 opioid receptors in other aspects of thermoregulation has been demonstrated (Handler et al., 1992, 1994; Spencer et al., 1988). Doses of BNTX that were ineffective versus SNC-80 antagonized morphine-evoked hypothermia, suggesting that delta1 receptors help to maintain the hypothermia initiated by mu receptor activation (Baker and Meert, 2002). Thus, the role of delta1 receptors may change during the progression of opioid-evoked effects, including hypothermia.

Limited information is available regarding endogenous systems which modulate delta opioid receptor-induced hypothermia, but nitric oxide and serotonin are clearly involved. Experiments indicate the hypothermic response to delta opioid, as well as kappa opioid (Benamar et al., 2002), receptor agonists require nitric oxide production (Rawls et al., 2006b). One potential mechanism is that the hypothermic response is linked directly to increased nitric oxide production (Gomez-Flores et al., 2001). A functional link between nitric oxide and delta receptors exists in opioid-induced gastric protection (Gyires, 1994), peripheral antinociception (Nozaki-Taguchi and Yamamoto, 1998 and Picolo and Cury, 2004), and immunological modulation (Gomez-Flores et al., 2001). Joint evidence that inhibition of nitric oxide synthase inhibits the hypothermia produced by both kappa and delta opioid receptor activation (Rawls et al., 2006b; Benamar et al., 2002) suggests that nitric oxide production might represent a final common pathway for the production of hypothermia, particularly that hypothermia mediated by opioid receptors. Another primary modulator of delta opioid receptor-induced hypothermia is serotonin. Pretreatment of rats with the 5-HT1A antagonist WAY 100635 (1 mg/kg, s.c.) attenuated the hypothermic effect of SNC-80 (35 mg/kg, i.p.). Administration of SNC-80 (35 mg/kg, i.p.) with non-hypothermic doses (2.5, 5 and 10 mg/kg, i.p.) of the selective serotonin reuptake inhibitor fluoxetine resulted in an enhancement of the hypothermic response (Rawls et al., 2006a). These data indicate that delta opioid receptor-induced hypothermia requires active 5-HT1Areceptors and is highly sensitive to the rate of 5-HT reuptake. It is known that 5-HT1A receptor activation causes hypothermia in rats and mice because WAY 100635 abolishes hypothermia produced by 5-HT agonists (Critchley et al., 1994; Fletcher et al., 1996; Forster et al., 1995). Because WAY 100635 also blocks a significant proportion of SNC-80-induced hypothermia, the hypothermic response to delta opioid receptor activation may produce downstream activation of 5-HT1A transmission, possibly through elevating extracellular 5-HT levels, which then contributes to the overall hypothermic effect of SNC-80. In vivo microdialysis data obtained from rats indicate that the level of extracellular 5-HT in the brains of conscious rats is increased by delta opioid receptor activation (Tao and Auerbach, 2002) and 5-HT reuptake block by fluoxetine (Perry and Fuller, 1992, 1993).

3.3. Mu opioid receptors and body temperature

In contrast to the hypothermic effect produced by kappa and delta opioid receptor activation, mu opioid receptor activation results in hyperthermia (Geller et al., 1982, 1983; Spencer et al., 1988; Adler and Geller, 1993; Rawls et al., 2003). The majority of early work investigating mu opioid receptor effects on body temperature used morphine. In experiments conducted in rats, morphine administered systemically at doses of 5–16 mg/kg produced significant hyperthermia whereas higher doses of morphine produced a biphasic response comprised of a brief hyperthermia followed by a pronounced and enduring hypothermia (Geller et al., 1982, 1983; Adler and Geller, 1993). Pretreatment of rats with naltrexone completely blocks the hyperthermic response to morphine, indicating that low doses of morphine produce hyperthermia through activation of mu opioid receptors (Geller et al., 1983;Chen et al., 1996; Rawls et al., 2003; Spencer et al., 1988). The importance of mu opioid receptors in the production of hyperthermia was further validated by experiments showing that the mu opioid agonists DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin) and PLO17 ([N-MePhe3,D- Pro4]morphiceptin), injected i.c.v. or directly into the POAH, induce hyperthermia that is blocked by the selective mu opioid receptor antagonists CTAP and beta-funaltrexamine (Appelbaum and Holtzman, 1986, Bradley et al., 1991; Adler and Geller, 1993;Handler et al., 1992; Spencer et al., 1988; Rawls et al., 2003).

More recent studies have used knockout mice to further investigate the role of mu opioid receptors in thermoregulation (Benamar et al., 2007a). Results from these experiments reveal that genetic deletion of the mu opioid receptor does not impact basal body temperature or circadian body temperature rhythm because both wild type and mu opioid receptor knockout mice displayed similar baseline body temperature and diurnal/nocturnal fluctuations. However, the hyperthermia produced by a low dose of morphine (1 mg/kg) was significantly greater in wildtype mice than in mu opioid receptor knockout mice (Benamar et al., 2007a). Genetic deletion of mu opioid receptor also significantly inhibited the hyperthermia produced by DAMGO.

Although the effects of morphine on thermoregulation are not entirely the same in rats and mice, the trends are similar in both species. For example, low doses of morphine produce hyperthermia and higher doses produce hypothermia (Baker and Meert, 2002). The hyperthermia results from mu opioid receptor activation, but the mechanism underlying the hypothermia remains unresolved. Experiments conducted in rats reveal that antisense oligonucleotides directed against kappa opioid receptors significantly attenuate the hypothermia induced by high morphine doses (Chen et al., 1996; Xin et al., 1997). However, neither morphine- nor fentanyl-induced hypothermia in mice is affected by pretreatment with the selective kappa opioid receptor antagonist nor-binaltorphimine (Baker and Meert, 2002). The non-selective opioid receptor antagonist naloxone does antagonize morphine- and fentanyl-induced hypothermia, indicating an opioid receptor mechanism, but evidence that the selective mu opioid receptor antagonist naloxonazine produces similar effects suggests that the effects of naloxone cannot be entirely attributed to antagonism. It is interesting to note that kappa opioid receptor antagonism cannot reverse a pre-existing hypothermia induced by morphine or fentanyl. If it is accepted that mu opioid receptors mediate hyperthermia and kappa opioid receptors mediate hypothermia (Xin et al., 1997), then it is likely that the modulatory roles of mu and kappa opioid receptors change during prolonged hypothermia. These changes may be part of a dynamic balance of opioid receptor occupation and the effect on receptor function of body temperature itself. The success of mu opioid, but not kappa opioid, receptor antagonism to reverse morphine- and fentanyl-induced hypothermia may also result from sudden receptor blockade producing rebound effects and upsetting this balance (Baker and Meert, 2002). Systemic mu opioid receptor blockade following morphine exposure produces a withdrawal-like stress response (Houshyar et al., 2001), an effect which may alter opioid regulation of body temperature. Naloxonazine, which blocks morphine- and fentanyl-evoked hypothermia as discussed above, binds selectively to mu1 opioid receptors, suggesting that these receptors are primarily responsible for the mu opioid effect. One final point worth mentioning is that doses of morphine which produce hyperthermia in unrestrained rats produce hypothermia in rats that are restrained (Martin et al., 1977). The exact mechanism underlying the influence of restraint stress is not clear, but it may be related to disruption of postural mechanisms which normally reduce heat loss (McDougal et al., 1983) or interference with GABA transmission (Del Rio-Garcia and Cremades, 1990).

A number of endogenous neurotransmitters modulate the thermoregulatory responses produced by mu opioid receptor activation. One recently identified messenger which impacts mu opioid responses is agmatine, a biogenic amine synthesized from arginine by the enzyme arginine decarboxylase and hydrolyzed by the enzyme agmatinase (Li et al., 1995). Agmatine is widely expressed throughout the brain, with the greatest concentrations detected in the midbrain (e.g. periaqueductal gray, locus coeruleus), cerebral cortex, hippocampus, amygdala, thalamus, striatum, and hypothalamic nuclei (Reis and Regunathan, 2000). Agmatine has been proposed to act as a neurotransmitter, and its brain concentrations correlate with that of other established neurotransmitters (Nguyen et al., 2003; Reis and Regunathan, 2000; Sastre et al., 1996). Agmatine interacts with multiple endogenous targets, including imidazoline sites, α2-adrenoceptors, nicotinic receptors, 5-HT3 receptors, NMDA receptors, and nitric oxide synthase (Piletz et al., 1995; Yang and Reis, 1999; Auguet et al., 1995; Loring, 1990; Su et al., 2003; Kolesnikov et al., 1996). Changes in body temperature are dependent on the level of endogenous agmatine because exogenous agmatine administration blocks the hyperthermia produced by a bacterial endotoxoin or restrain stress (Aricioglu and Regunathan, 2005). It was subsequently shown that agmatine administration (50 mg/kg) also inhibited a significant proportion of morphine-induced hyperthermia in rats (Rawls et al., 2007a). Pretreatment of rats with idazoxan (5 mg/kg, i.p.), a mixed imidazoline/α2-adrenoeceptor antagonist, completely abolished the ability of agmatine to reduce morphine-evoked hyperthermia. In contrast, pretreatment with yohimbine, a selective α2-adrenoeceptor antagonist, was ineffective. The ability of idazoxan to antagonize the attenuation of morphine-evoked hyperthermia by agmatine, coupled with the ineffectiveness of yohimbine, suggests imidazoline site activation mediated the effects of agmatine. Although agmatine efficacy versus morphine-induced hyperthermia appears to be highly dependent on imidazoline site activation, downstream increases in NMDA receptor activity or nitric oxide signaling cannot be excluded from the mechanism. The hyperthermic effect of morphine is reduced by pharmacological antagonism of NMDA receptors, indicating that active NMDA receptors are required for the response (Rawls et al., 2003). Agmatine acts as a competitive antagonist at NMDA receptors, and the systemic administration of agmatine at doses which block morphine-evoked hyperthermia also inhibit seizure-induced extracellular glutamate levels in frontal cortex of rats (Olmos et al., 1999).

Mu opioid receptors within the POAH have been found to be involved in the fever induced by interleukin-6 (IL-6) (Benamar et al., 2002), as the pretreatment with the selective mu-opioid receptor antagonist, cyclic D-phe-Cys-Try-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), significantly blocked the IL-6-induced fever. Mu opioid receptors are also implicated in the pathogenesis of the bacterial LPS fever. Pretreatment with the selective mu-opioid antagonist (CTAP), into the preoptic anterior hypothalamus, reduced the fever induced by lipopolysaccharide (LPS) (Benamar et al., 2000). Moreover, LPS failed to produce fever in mice lacking the mu opioid receptor (Benamar et al., 2005). The i.c.v. injection of LPS produced a dose-dependent, significant elevation in body temperature in WT (Benamar et al., 2007a). One study has suggested that transfer of LPS from the brain into the periphery in significant amounts is what accounts for the observed effects of i.c.v. LPS (Cunningham et al., 2005). It is highly unlikely that the small amount of LPS (100 ng) injected via the i.c.v. route evoked fever through its leakage into the systemic compartment, because the same amount of LPS, when injected peripherally, did not evoke fever, even at a dose 10 times higher (Benamar et al., 2007a).

5. 1. Cannabinoid ligands and receptors

Ever since the identification of tetrahydrocannabinol (Δ9-THC) as the primary psychoactive constituent of marijuana in 1967 (Mechoulam et al., 1967), a number of cannabinoid agonists and antagonists such as the aminoalkylindole (R)-(+)-[2,3-Dihydro-5-methyl-3-(4 morpholinylmethyl)pyrrolo[1,2,3-de)-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55212-2); 2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940); and (6aR,10aR)-9-(Hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol (HU-210), have been now been designed, synthesized, and tested in animals (Mechoulam et al., 1988; Rinaldi-Carmona et al., 1996, 1998; Compton et al., 1992, 1996). Cannabinoids produce an array of pharmacological effects in animals, including but not limited to hypothermia, sedation, catalepsy, analgesia, motor impairment, and cognitive dysfunction (Abood and Martin, 1992).

The most exciting development in cannabinoid research over the past two decades is the discovery of an endogenous cannabinoid system. This system is comprised of three components: (1) cannabinoid receptors, called cannabinoid CB1 and cannabinoid CB2, which mediate the pharmacological actions of cannabinoid agonists; (2) endogenously produced cannabinoid-like substances which mimic the actions of exogenously administered cannabinoid agonists; and (3) hydrolytic enzymes which inactivate endogenous cannabinoids (Matsuda et al., 1990; Devane et al., 1992). Both CB1 and CB2 receptors inhibit adenylyl cylcase activity and mitogen-activated protein kinases (MAPK) through coupling to inhibitory G-proteins (Gi/o) (Howlett, 2005). The early belief that CB1 and CB2 receptors were expressed almost exclusively in the brain and periphery, respectively, has changed now changed. CB1 receptors, in addition to being expressed at high levels in the brain, are also expressed in peripheral organs such as the liver (Osei-Hyiaman et al., 2005). The existence of CB2receptors in the brain was initially discounted except for inflammatory conditions. It is now known that CB2 receptors, in addition to being located on peripheral mast cells, are expressed in the brain under both normal and inflammatory conditions (Ashton and Glass, 2007; Van Sickle et al., 2005;Brusco et al., 2008). Endogenous cannabinoids include anandamide (N-arachidonoyl-ethanloamine), 2-arachidonoyl-glycerol (2-AG), 2-arachidonyl-glycerol ether (noladin ether), N-arachidonoyl-dopamine (NADA), and virodhamine (Devane et al., 1992; Mechoulam et al., 1995; Sugiura and Waku, 1995; Hanus et al., 2001; Bisogno et al., 2000). Anandamide and 2-AG display high affinity for CB1 and CB2 receptors, but the pharmacological activities of the more recently proposed endogenous cannabinoids is yet to be determined. In addition to the endogenous substances which activate cannabinoid receptors, the first endogenous CB1 antagonist, hemopressin, was discovered recently (Heimann et al., 2007). Degradation of endogenous cannabinoids which leads to inactivation of their biological effects is mediated by two different classes of enzymes called fatty acid amide hydrolase (FAAH) and monacylglycerol lipase (MAGL) (Cravatt et al.,1996; Karlsson et al., 1997). Discovery of the endogenous cannabinoid system has prompted development and characterization of pharmacological probes to better investigate cannabinoid pharmacology. These probes include endogenous cannabinoid uptake inhibitors (e.g. AM404, VDM11, OMDM-1); FAAH inhibitors; MAGL inhibitors; anandamide analogues (e.g. methanandamide) that are more resistant to enzymatic hydrolysis than anandamide; mixed CB1/CB2 agonists (e.g. WIN 55212-2, HU-210); selective CB1 antagonists/inverse agonists (e.g. SR 141716A, AM251); neutral CB1antagonists; and selective CB2 antagonists/inverse agonists (e.g. SR 144528) (Di Marzo, 2009). Cannabinoid receptors are not limited to CB1 and CB2. The orphan G-protein coupled receptor (GPR55) has attracted much attention as another member of the cannabinoid family, potentially explaining physiological effects that are not mediated by CB1 and CB2 receptors (Johns et al., 2007;Ryberg et al., 2007). In vivo pharmacological evidence suggests that development of antagonists targeting the novel receptor may result in medications to treat osteoporosis, inflammation, and neuropathic pain (Bab and Zimmer, 2008; Staton et al., 2008; Whyte et al., 2009). At this point, however, at least to our knowledge, there is no published evidence that GPR55 receptor activation or antagonism produces physiologically significant changes in body temperature. It is worth noting, nevertheless, that GPR55 receptor expression has been detected in subdivisions of the hypothalamus that regulate body temperature, although the highest levels of expression are found in the hippocampus and striatum (Ryberg et al., 2007; Sawzdargo et al., 1999). The localization of GPR55 receptors in thermoregulatory centers, as well as their involvement in the inflammatory response, does raise the possibility that they may play a role in thermoregulation, perhaps at it relates to the febrile response.

5.2. Cannabinoid agonists produce hypothermia

Δ9-THC administration induces profound hypothermia in animals (Pertwee, 1974; Pertwee and Tavendale, 1977; Fennessy and Taylor, 1977; Englert et al., 1973). The hypothermia produced by Δ9-THC is accompanied by a reduction in oxygen consumption, which indicates reduced heat production, as opposed to increased heat loss, is primarily responsible for the hypothermic response (Fitton and Pertwee, 1982). The hypothermic effect of Δ9-THC is mimicked by cannabinoid agonists. A wide variety of species, including rats, mice, and primates, display hypothermia following acute cannabinoid agonist administration (Compton et al., 1992; Fan et al., 1994; Spina et al., 1998; Fox et al., 2001; Rawls et al., 2002a). The hypothermic response to WIN 55212-2 has been particularly well characterized. Following systemic administration to rats and mice, WIN 55212-2 (1, 2.5, 5, or 10 mg/kg) produces a hypothermia that is rapid in onset, persistent for 3–4 hours, dose-dependent, and completely prevented by CB1 receptor antagonism (Rawls et al., 2002a, 2004a, b, 2006a, b,c; Compton et al., 1992; Devry et al., 2004). Cannabinoid agonists do not evoke hypothermia in mice lacking CB1 receptors, a finding which underscores the widely held belief that CB1 receptor activation is the primary mechanism by which cannabinoid agonists decrease body temperature (Ledent et al., 1999;Zimmer et al., 1999). The hypothermic effect of WIN 55212-2 and other cannabinoids is not affected by CB2 receptor antagonists, a finding that is entirely consistent with the tenet that CB2 receptors play little, if any, role in the cannabinoid-induced hypothermia (McGregor et al., 1996; Nava et al., 2000;Fox et al., 2001; Wiley et al., 1995).

Multiple brain sites contribute to the hypothermic effect produced by systemically administered cannabinoid agonists. One region that plays a critical role is the POAH (Xin et al., 1997). The POAH contains a large population of thermosensitive neurons which receive and integrate information from central and peripheral sensors and then transmit the modulating signal to thermoregulatory effectors that maintain body temperature around a set-point temperature. A consistent finding across multiple research groups is that POAH activation is absolutely required for cannabinoid agonists to produce hypothermia. The most obvious evidence is that a rapid and dose-dependent hypothermia is detected following the direct injection of cannabinoid agonists into the POAH. The hypothermic response is independent of the chemical structure of the cannabinoid because the effect is produced by three structurally different cannabinoids – Δ9-THC, WIN 55212-2, and HU-210 (Fitton and Pertwee, 1982; Rawls et al., 2002; Ovadia et al., 1995). The hypothermia produced following the direct injection of WIN 55212-2 into the POAH is prevented by the systemic administration of the selective CB1 antagonist SR 141716A (Rawls et al., 2002a). The effectiveness of SR 141716A indicates CB1receptors in the POAH are responsible for the effect, an interpretation supported by binding and immunohistochemical data which indicate that CB1receptor density in the POAH is among the highest of any brain region (Herkenham et al., 1991; Mailleux and Vanderhaeghen, 1992; Moldrich and Wenger, 2000; Pettit et al., 1998; Tsou et al., 1998).

An even closer inspection of how cannabinoid-induced hypothermia varies with administration route provides clues about the anatomic sites which mediate cannabinoid-induced hypothermia. Both systemic and intra-POAH administration of WIN 55212-2 produces hypothermia (Rawls et al., 2002a). A notable difference between the administration routes is the duration of hypothermia. Systemically administered WIN 55212-2 produces hypothermia that endures for 3–4 hours whereas the intra-POAH injection of WIN 55212-2 induced hypothermia which persists for only about 60 min. Another difference between injection routes is the magnitude of the hypothermia, which is much greater following systemic administration. One final feature of the hypothermia that is sensitive to administration route is the time point at which maximal hypothermia is detected. Systemic injection of WIN 55212-2 produced maximal hypothermia 60–90 min post-administration whereas intra-POAH WIN 55212 produces peak hypothermia 30 min post-injection (Rawls et al., 2002a). Evidence that three aspects (duration, magnitude, maximal effect) of WIN 55212-2-induced hypothermia are sensitive to administration route indicates that other brain regions, in addition to the POAH, contribute to the hypothermia. One possibility is that different brain regions contribute to different stages of the hypothermic response. For example, CB1 receptor activation in the POAH may be the primary trigger for initiating the hypothermic response whereas recruitment of extra-hypothalamic areas may underlie maintenance of the hypothermia. A related question is whether or not CB1 receptor-containing neurons in the POAH are intrinsic or extrinsic to the region. Romero et al. (1998) suggested that cannabinoid receptor-containing neurons are all intrinsic to the hypothalamic nuclei because hypothalamic deafferentation did not alter cannabinoid receptor binding. CB1 receptors are densely expressed in extrahypothalamic sites where cannabinoid systems produce hypothermia and interact with been neurotransmitter systems which regulate body temperature (Herkenham et al., 1991; Chaperon and Thiebot, 1999; Schmeling and Hosko, 1980; Fitton and Pertwee, 1982). The most likely conclusion is that cannabinoid-induced hypothermia is dependent on processes in hypothalamic and extrahypothalamic substrates.

5.3. Endogenous cannabinoid and vanilloid effects on body temperature

Unlike the opioid system, where mu and kappa opioid receptors are in tonic balance and mediate hyperthermia and hypothermia, respectively (Xin et al., 1997), a role for the endogenous cannabinoid system in the tonic regulation of body temperature has not been clearly defined. It is a consistent finding across different research groups that selective CB1 or CB2 receptor antagonists, even when administered at high doses, do not produce significant changes in body temperature in rodents (Rawls et al., 2002a; Compton et al., 1996; McGregor et al., 1996; Nava et al., 2000). These findings are in direct contrast to the effects of opioid receptor antagonists and transient receptor potential channel (TRP) antagonists (i.e., TRPV1), both of which produce changes in body temperature across a wide variety of species, including humans (Gavva, 2008). The ineffectiveness of cannabinoid antagonists does not support a critical role for CB1 or CB2 receptors in the tonic regulation of body temperature regulation, in spite of evidence that several other biological endpoints, such as inflammatory hyperalgesia and antinociception, are impacted by an endocannabinoid tone (Calignano et al., 1998; Welch et al., 1998). Based on the widespread belief that CB2 receptors have little, in any, role in thermoregulation, it is not unexpected that CB2 receptor antagonism does not alter basal body temperature. It is more challenging to explain the ineffectiveness of CB1 receptor antagonists considering the profound hypothermia that exogenously administered cannabinoid agonists produce through CB1 receptor activation (Compton et al., 1996; Rawls et al., 2002a). The majority of thermoregulatory studies have used cannabinoid receptor antagonists (e.g. SR 141716A and AM 251) which also possess inverse agonist properties. It is possible that detection of tonic body temperature regulation by CB1 receptors was masked by the inverse agonist properties of these antagonists or by the sensitivity of the body temperature assay itself. Experiments with neutral, selective CB1 receptor antagonists (e.g. AM 4113) which lack inverse agonist properties may be useful in addressing this possibility. Such neutral antagonists may be more useful than inverse agonists as pharmacological tools because they would produce effects only in the presence of elevated endocannabinoid levels (Hodge et al., 2008; Sink et al., 2009).

Cannabinoid receptor antagonists are not the only pharmacological tools used to investigate endocannabinoid effects on body temperature. Compounds that block endocannabinoid uptake and hydrolysis are equally attractive agents (Di Marzo, 1999, Dinh et al., 2002; Freund et al., 2003). One of the earliest examples of such a compound is AM-404 [N-(4-hydroxyphenyl)-arachidonylethanolamide], which blocks endogenous cannabinoid transport across cell membranes and enhances CB1 receptor-mediated effects by increasing the extracellular concentration of endocannabinoids (Beltramo et al., 1997, Beltramo et al., 2000; Calignano et al., 1997). Despite the impact of AM 404 on endocannabinoid signaling, it is now apparent that the biological effects produced by this pharmacologically rich agent are not exclusively confined to the endocannabinoid system. Sites of action of AM-404 include TRPV1receptors, calcium channels, sodium channels, cannabinoid receptors, and a novel N-acyl fatty acid-sensitive receptor (Zygmunt et al., 2000, Kelley and Thayer, 2004, Nicholson et al., 2003, Hajos et al., 2004, Chen et al., 2001,Jonsson et al., 2003; van der Stelt and Di Marzo, 2003). Body temperature experiments reveal that AM 404 (1, 5, 10 and 20 mg/kg, i.p.) produces robust hypothermia in rats following peripheral administration. The hypothermia is completely abolished by pretreatment with two structurally distinct TRPV1receptor antagonists, capsazepine (30 mg/kg, i.p.) and SB 366791 (2 mg/kg, i.p.). Pretreatment with SR 141716A or a fatty acid amide hydrolase (FAAH) inhibitor, AA-5-HT, does not affect AM 404-induced hypothermia (Rawls et al., 2006c). Those results indicate AM 404-induced hypothermia is dependent on TRPV1 receptor activation but not cannabinoid CB1 receptor activation. A TRPV1 receptor mechanism of action for AM 404 is supported by evidences that AM 404 acts as a full agonist at both rat and human recombinant TRPV1receptors (De Petrocellis et al., 2000; Ross et al., 2001) and that TRPV1 receptor activation by capsaicin induces pronounced hypothermia in rodents (Miller et al., 1982; Hayes et al., 1984; Rawls et al., 2006c; Ding et al., 2005).

An exact mechanism is difficult to identify due to the pharmacological diversity of AM 404, but the most conceivable explanation is that AM-404 acts through a capsaicin-like process to produce hypothermia by directly activating TRPV1receptors. The same two antagonists, capsazepine and SB 366791, which block AM 404-induced hypothermia also inhibit capsaicin-evoked hypothermia (Dogan et al., 2004; Varga et al., 2005). It cannot be completely discounted that AM 404 acts as an indirect TRPV1 receptor agonist by preventing anandamide uptake and increasing the extracellular concentration of anandamide, but this mechanism is unlikely because: (1) the binding site for TRPV1 ligands is intracellular (De Petrocellis et al., 2001), indicating that an uptake block produced by AM 404 would lead to an increase in anandamide levels on side of the membrane (extracellular face) opposite to that of the TRPV1 binding site (intracellular); (2) inhibition of the anandamide plasma membrane transporter prevents, rather than enhances, anandamide efficacy at TRPV1 receptors (De Petrocellis et al., 2001); and (3) SR 141716A prevents anandamide-induced hypothermia in rats but is ineffective versus AM 404-induced hypothermia, suggesting the two compounds (anandamide and AM 404) produce hypothermia through mechanisms which are not entirely the same (Costa et al., 1999; Rawls et al., 2006c).

Although anandamide can activate both cannabinoid and TRPV1 receptors, its hypothermic effect appears to be mediated by CB1 receptor activation (Costa et al., 1999; Rawls et al., 2006b). This conclusion is based on evidence that anandamide (20 mg/kg, i.p.) produces hypothermia in rats which is abolished by pretreatment with SR 141716A (5 mg/kg, i.p.) but not by pretreatment with SB 366791 (2 mg/kg, i.p.) (Rawls et al., 2006c). Because higher anandamide concentrations are required to activate TRPV1 receptors compared to CB1receptors (Zygmunt et al., 1999), it is possible that anandamide-induced hypothermia would display sensitivity to TRPV1 receptor blockade in a different experimental paradigm, such as one in which higher systemic doses of anandamide (e.g. 40 mg/kg) were tested or one in which anandamide was administered in combination with a FAAH inhibitor to prolong its half-life and preserve its biological activity. Nonetheless, evidence that the hypothermic effect of anandamide is mediated by CB1 receptor activation and that the hypothermic effect of AM 404 is mediated by TRPV1 receptor activation suggests the two agents produce hypothermia by different mechanisms of action.

TRPV1 receptors have garnered much recent attention for their key role in tonic body temperature regulation (Gavva, 2008). Unlike CB1 receptor antagonists (Rinaldi-Carmona et al., 1996; Rawls et al., 2002a), TRPV1 receptor antagonists produce hyperthermia in multiple species (rats, dogs, and monkeys), including humans, humans following their systemic administration (Gavva et al., 2007;Gavva, 2008; Wong and Gavva, 2008). These findings indicate TRPV1 function in thermoregulation is conserved from rodents to primates. Peripheral restriction of the TRPV1 antagonists did not eliminate their ability to produce hyperthermia, thus indicating that their site of action is predominantly outside of the blood-brain barrier. TRPV1 antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. These novel findings have led to the widespread belief that body temperature maintenance is the primary function of TRPV1 receptors (Gavva, 2008).

The mechanism of tonic TRPV1 receptor activation is unclear, but enhanced phosphorylation of certain intracellular residues on the TRPV1 receptor produced by the combined actions of multiple endogenous TRPV1 agonists, including oleoyldopamine, NADA, and low pH may play a role (Premkumar and Ahern, 2000). Other transient receptor potential (TRP) channels, such as TRPA1, TRPM8, TRPV3, and TRPV4, may also tonically regulate body temperature. The TRPA1 and TRPM8 agonist icilin produces dose-dependent hyperthermia in rats following systemic administration (Ding et al., 2008). The hyperthermia produced following TRPA1/TRPM8 activation is directly opposite to the hypothermia produced following TRPV1 receptor activation by capsaicin (Varga et al., 2005; Miller et al., 1982; Hayes et al., 1984), findings that are consistent with the classification of TRPA1 and TRPM8 receptors as cold channels and TRPV1 receptors as warm channels. Events triggered by capsaicin include both heat loss and heat production mechanisms and involve a number of endogenous substances such as glutamate, monoamines and substance P (Caterina, 2007). Icilin, on the other hand, activates TRP channels (TRPM8 and TRPA1) that respond to cold. The hyperthermic effect of icilin produces a dose-related hyperthermia is consistent with the effects of menthol, another cold channel agonist which also causes hyperthermia in rats (Ruskin et al., 2007). The most obvious difference in the hyperthermic effects of icilin and menthol is that icilin produces a hyperthermia that is greater in magnitude and persistence than menthol, perhaps related to evidence that icilin activates both TRPM8 and TRPA1 receptors whereas menthol only activates TRPM8 receptors (McKemy et al., 2002; Peier et al., 2002; Story et al., 2003; Bandell et al., 2004).

Evidence also indicates that icilin acts outside of the brain to produce hyperthermia because icilin injected into the ventricles does not affect body temperature (Ding et al., 2008). A peripheral site of action is consistent with data showing that icilin acts outside of the brain to evoke wet dog shakes and that TRPM8 and TRPA1 channels are located outside of the brain, primarily on sensory neurons that project to dorsal root ganglia neurons in the spinal cord and trigeminal neurons in the brain (Wei and Seid, 1983; McKemy et al., 2002;Peier et al., 2002; Reid et al., 2002; Reid and Flonta, 2002; Nealen et al., 2003;Thut et al., 2003; Story et al., 2003). One interpretation is that stimulation of peripheral cold-activated channels by icilin provides a signal to thermoregulatory centers located in the brain. This signal then is capable of triggering an elevation in body temperature, presumably through alterations in glutamate- and nitric oxide-based mechanisms that regulate heat production and heat loss (Ding et al., 2008). This explanation is consistent with the view that TRPM8-deficient mice have a specific impairment in sensing cold temperatures which is manifested as a reduced avoidance of cold temperatures relative to wild-type mice (Dhaka et al., 2007). Another hallmark effect of icilin is the production of wet-dog shakes (WDS), and the relationship between icilin-induced hyperthermia and wet-dog shaking is still not clear (Wei, 1976). The critical question is whether WDS occurs as a result of the hyperthermia or vice versa. Both effects of icilin are sensitive to administration route. Hyperthermia is detected following intraperitoneal or intramuscular injection whereas shaking is produced only following intraperitoneal administration (Wei, 1976;Werkheiser et al., 2006, 2007; Ding et al., 2008). This data indicates that hyperthermia is produced in the absence of shaking but that shaking is detected only when hyperthermia is present. It is possible that hyperthermia triggers the shaking through a “heat gain” or shivering response (Wei, 1976). Another possibility is that a metabolite of the parent compound icilin, formed following its intraperitoneal administration, causes the shaking whereas icilin itself produces the hyperthermia. Alternatively, the shaking could be the result of a local effect of icilin within the peritoneum. Future studies will need to delineate the relationship between the two hallmark responses to better determine the mechanism of action of icilin and the roles of TRPA1 and TRPM8 receptors in thermoregulation.

5.4. Cannabinoid interactions and body temperature

Thermoregulation is a multifactorial process involving interactions between multiple endogenous systems. It is not surprising that cannabinoid-induced hypothermia is influenced by multiple neurotransmitters and messengers, including but not limited to glutamate, nitric oxide, GABA, agmatine, serotonin, opioids, chemokines and nociceptin (Rawls et al., 2002a, c; Benamar et al., 2009; Malone and Taylor, 1998, 2001; Fennessy and Taylor, 1978). Glutamate is the major excitatory neurotransmitter in the mammalian brain and plays a key role in cannabinoid-induced hypothermia (Rawls et al., 2002c), as well as other pharmacologial effects of cannabinoids such as antinociception and catalepsy (Kinoshita et al., 1994; Kelly and Chapman, 2001; Palazzo et al., 2001). Glutamate administered by itself causes hyperthermia (Yakimova and Ovtcharov, 1989; Singh and Gupta, 1997; Huang et al., 2001). Antagonists that block NMDA receptors can produce hypothermia (Corbett et al., 1990; Farfel and Seiden, 1995; Bhargava and Thorat, 1997) or hyperthermia (Pechnick et al., 1989) depending on the dose of antagonist tested.

For combination studies with cannabinoids, NMDA receptor antagonists enhance hypothermia produced by the cannabinoid agonist WIN 55212-2 (Rawls et al., 2002c). The effect on WIN 55212-2 is produced by a noncompetitive (dextromethorphan) and competitive [(−)-6-[phosphonomethyl-1,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-2-carboxylate]] ((LY 235959) NMDA antagonist. Both dextromethorphan (5–75 mg/kg i.m.) and LY 235959 1–4 mg/kg i.m.) produce dose-related hypothermia in rats. However, what is most interesting is that a non-hypothermic dose of dextromethorphan (10 mg/kg) augmented the hypothermia produced by WIN 55212-2 (1, 2.5, or 5 mg/kg). The enhancement produced by dextromethorphan was pronounced, and joint-action analysis indicated that the drug-drug interaction between dextromethorphan and WIN 55212-2 was strongly synergistic. That is, the relative potency of WIN 55212-2 was enhanced about 3-fold when administered in combination with dextromethorphan. A non-hypothermic dose of LY 235959 (1 mg/kg) produced a similar enhancement in WIN 55212-2-induced hypothermia, thus confirming the hypothermic synergy. The results with LY 235959, a water-soluble compound with much greater selectivity for NMDA receptors than dextromethorphan, also indicate that receptor level interactions between CB1 and NMDA receptors underlie the synergy.

Despite the chemical and pharmacological differences between dextromethorphan and LY 235959, their qualitatively and quantitatively similar enhancements of cannabinoid-induced hypothermia suggest a common mechanism – NMDA receptor activation –mediates the synergy. One aspect of the NMDA-CB1 receptor synergy which remains unclear is the exact mechanism. A likely explanation is that WIN 55212-2 produces hypothermia by decreasing the level of extracellular glutamate in one or more brain regions (e.g. hypothalamus) which control body temperature. Because glutamate administration itself produces hyperthermia, presumably by increasing endogenous glutamate levels and enhancing glutamate transmission at NMDA receptors, it can be predicted that a reduction in extracellular glutamate produced by the systemic administration of WIN 55212-2 would produce the exact opposite effect, a reduction in glutamate transmission at NMDA receptors. In the case in which WIN 55212-2 is administered by itself, the reduced NMDA receptor activity would remove the hyperthermic tone normally mediated by endogenous glutamate. When WIN 55212-2 is administered in the presence of a NMDA receptor antagonist, its hypothermic effect may be further enhanced due to the combination of reduced extracellular glutamate (produced by WIN 55212-2) and direct NMDA receptor blockade (produced by LY 235959 or dextromethorphan). This interpretation is consistent with the widely held tenet that CB1 receptor activation inhibits glutamate transmission in the brain (Hajoset al., 2001; Shen et al., 1996; Howlett, 1984; Mackie and Hille, 1992).

Nitric oxide also impacts cannabinoid-induced hypothermia. Considering the direct relation between nitric oxide production and NMDA receptor activation and the aforementioned role of NMDA receptors in cannabinoid-evoked hypothermia, it is not surprising that the nitric oxide system also plays such a critical role. NMDA receptor stimulation increases nitric oxide production through a mechanism involving increased calcium ion influx into the cell and a subsequent elevation in intracellular calcium ion concentration, which in turns leads to activation of calcium-dependent nitric oxide synthases. Akin to NMDA receptor antagonism, inhibition of nitric oxide production during WIN 55212-2 administration enhances cannabinoid-induced hypothermia (Rawls et al.2004a). A non-hypothermic dose of L-NAME (50 mg/kg) augments the hypothermia produced by progressively increasing doses of WIN 55212-2 (0.5–5 mg/kg). Joint-action analysis indicates the relative potency of WIN 55212-2 is enhanced 2.5-fold when administered in the presence of L-NAME, thus revealing that the drug-drug interaction between L-NAME and WIN 55212-2 is synergistic rather than simply additive (Tallarida, 2001). The hypothermic synergy is not produced by co-administration of L-NAME and the inactive enantiomer of WIN 55212-2, WIN 55212-3 [S-(−)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate] (5 mg/kg, i.m.), which confirms the synergistic interaction is due to cannabinoid receptor activation as opposed to a non-specific effect of WIN 55212-2.

The mechanism and site underlying the hypothermic synergy has not yet been identified. A central site of action is likely due to the overwhelming evidence that cannabinoids act in the brain, through a CB1 receptor mechanism, to induce hypothermia (Fitton and Pertwee, 1982; Compton et al., 1992; Fan et al., 1994;Howlett, 1995; Ovadia et al., 1995; Rawls et al., 2002a). Furthermore, CB1receptor-expressing neurons located in thermosensitive brain regions express high levels of nitric oxide synthase (Bredt and Snyder, 1992; Azad et al., 2001). One possibility is that the marked hypothermia produced by WIN 55212-2 caused a compensatory increase in nitric oxide production, perhaps as a mechanism to counter the pronounced decline in body temperature. In the case in which the cannabinoid agonist is administered with a nitric oxide synthase inhibitor (L-NAME), this normal compensatory response resulting from an increase in nitric oxide production is blocked, leading to an exaggerated hypothermia. This mechanism is entirely dependent on two factors. One is that that cannabinoid agonists increase the endogenous concentration of nitric oxide, either by increasing its synthesis or slowing its degradation. Endogenous cannabinoids do stimulate nitric oxide release in rat kidneys, invertebrate nerve ganglia, and human immune tissue (Deutsch et al., 1997; Stefano et al., 1997,2000).

The second requirement is that an elevation in nitric oxide levels is indeed capable of counteracting cannabinoid-induced hypothermia, either by producing a hyperthermia that simply opposes the hypothermia or by inhibiting downstream signaling triggered by CB1 receptor activation. Nitric oxide production has been shown to produce hyperthermia, but the results are inconsistent. Some studies have demonstrated that nitric oxide participates in fever generation (Lin and Lin, 1996; Scammell et al., 1996; Roth et al., 1998;Benamar et al., 2001) whereas others have shown that nitric oxide displays antipyretic properties and participates in the production of hypothermia (Moncada et al., 1991; Gourine, 1995; Branco et al., 1997; Steiner et al., 1998;Almeida and Branco, 2001; Benamar et al., 2002).

It is important to note that enhancement of cannabinoid responses by inhibition of nitric oxide production has been demonstrated previously, as L-NAME potentiates inhibition of contractile responses in rats produced by endogenous cannabinoids (Mendizabal et al., 2001). Because both NMDA receptor antagonism and nitric oxide synthase inhibition enhance cannabinoid-induced hypothermia, it is tempting to speculate that inhibition of the NMDA/nitric oxide signaling pathway underlies the enhancement. If this is true, then cannabinoid agonists would be expected to produce qualitatively similar effects on NMDA receptor and nitric oxide synthase activity. It is a consensus across more than a decade of research that cannabinoid agonists inhibit glutamate release. Such an effect might be predicted to a reduction in extracellular glutamate and excitatory drive onto NMDA receptors, leading to a reduction in NMDA receptor activity and downstream nitric oxide production. WIN 55212-2 has been shown to suppress potassium-evoked neuronal nitric oxide synthase activity (Hillard et al., 1999).

Considering the impact of excitatory transmission on the hypothermic response to cannabinoids, it is not surprising that GABA-mediated inhibitory pathways also play a role (Rawls et al., 2004b). Glutamate and GABA systems oppositely modulate cannabinoid-induced hypothermia, with increased glutamate activity opposing the hypothermia and increased GABA activity facilitating the hypothermia. GABA is the principal inhibitory neurotransmitter in the mammalian brain, where it is exclusively synthesized from glutamate by glutamic acid decarboxylase. It acts through three GABA receptor subtypes, GABAA, GABAB, and GABAC (Chebib and Johnston, 1999). Ionotropic GABAAreceptor activation produces an increased chloride conductance and membrane hyperpolarization (Sieghart et al., 1992) whereas metabotropic GABABreceptors mediate intracellular effects through a G-protein-coupled mechanism following activation (Chebib and Johnston, 1999).

In regard to thermoregulation, injection of GABA or the GABAA agonist muscimol induces hypothermia in rats (Zarrindast and Oveissi, 1988;Sancibrian et al., 1991). Effects of GABAB receptor activation are mixed, with both hypothermic and hyperthermic responses reported following baclofen administration (Zarrindast and Oveissi, 1988; Sancibrian et al., 1991; Phillis et al., 2001). Evidence indicates the hypothermia produced by GABA and CB1receptor activation is mediated by overlapping pathways. For example, GABA receptors are densely located in thermosensitive hypothalamic regions which express CB1 receptor immunoreactivity (Moldrich and Wenger, 2000; Jha et al., 2001a, b; Okamura et al., 1990). Pharmacological studies have demonstrated that GABA agonists enhance cannabinoid-evoked hypothermia (Pertwee et al., 1991; Pertwee and Greentree, 1988; Pertwee et al., 1988a, b). GABAB receptors do not appear to play an important role because pretreatment of rats with the GABAB antagonist SCH 50911 (1–10 mg/kg i.p.) does not alter WIN 55212-2-induced hypothermia. The hypothermia is dependent on GABAA receptor activation because pretreatment with the GABAA antagonist bicuculline (2 mg/kg, i.p.) inhibits hypothermia produced by WIN 55212-2 (Rawls et al., 2004b). The converse is not true as cannabinoid CB1 receptor antagonism with SR 141716A (2.5 mg/kg, i.m.) does not alter hypothermia produced by either GABAA receptor activation by muscimol (2.5 mg/kg, i.p.) or GABAB receptor activation by baclofen (5 mg/kg, i.p.). The combined data indicate cannabinoid agonists produce hypothermia which is dependent on downstream GABAAreceptor activation but that CB1 receptor signaling is not required for GABA agonists to induce hypothermia.

Similar to its effects on mu opioid responses, agmatine also modulates pharmacological effects of cannabinoids, including their hypothermic and analgesic actions (Rawls et al., 2006d, Aggarwal et al., 2009). Both the hypothermic and analgesic effects of cannabinoid agonists are enhanced by exogenous agmatine. Changes in body temperature are not detected following administration of agmatine (10, 25 and 50 mg/kg, i.p.) by itself. Co-administration of agmatine (50 mg/kg, i.p.) and WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.) results in an enhancement of the hypothermic response. Joint-action analysis indicates the relative potency of WIN 55212-2 is increased 2.7-fold in the presence of agmatine, indicating the drug-drug interaction between agmatine and WIN 55212-2 is synergistic. Agmatine injected directly into the lateral ventricle (25 and 50 µg/rat, i.c.v.) produces an enhancement of WIN 55212-2-induced hypothermia which is remarkably similar to that produced by systemically injected agmatine. The congruent effect of agmatine following systemic and ventricular administration identifies the brain as the site of action of agmatine. It is not yet clear whether or not agmatine administration controls effects produced by long-term exposure to cannabinoids. As discussed earlier, agmatine administration blocks the physical dependence, analgesic tolerance, and rewarding effects produced by repeated morphine exposure. Unpublished observations from our laboratory suggest that agmatine administration is capable of blocking the development, but not the expression of hypothermic tolerance, produced by repeated WIN 55212-2 administration.

A novel finding is that cannabinoids modulate LPS-induced fever (Benamar et al., 2007b). Cannabinoids and LPS both affect the immune and thermoregulatory systems. Non-hypothermic doses of WIN 55,212-2 significantly reduce LPS-induced fever in rats (Benamar et al., 2007b). This inhibitory effect is not due to a nonspecific interaction with hydrophobic regions of functional proteins or their lipid surroundings in the cell membrane because WIN 55,212-3, an enantiomer of WIN 55,212-2, does not affect the LPS-induced fever, indicating that the effect of WIN 55,212-2 on LPS-induced fever is stereoselective. Δ9-THC injected at doses of 0.5 or 1 mg/kg also attenuates LPS-induced fever in a manner similar to WIN 55212-2. Cytokines (e.g. IL-6) act as endogenous pyrogens and play an important role in the mechanisms responsible for the development of the febrile response during infection and inflammation (Kluger et al., 1995). Because cannabinoids display immunosuppressive effects, the inhibition of LPS-induced fever by WIN 55212-2 may be due to a reduction of IL-6 produced during the LPS-induced fever and a reduction of the fever. SR141716A prevents the WIN 55,212-2 effects on LPS-induced fever, indicating that a CB1 receptor mechanism mediated the response (Benamar et al., 2007b).

Because cytokines are released in response to LPS, and the CB2 receptor has a modulatory role in the immune system, including the cytokine network (Klein et al., 1998), it is tempting to speculate that CB2 receptors also contribute to the LPS-induced fever as well, but SR144528 does not alter the inhibitory effect of WIN 55212-2 on LPS-induced fever (Benamar et al., 2007b). Benamar and colleagues (2009) have recently provided the first in vivo evidence of a physiological interaction between cannabinoid and chemokine systems. One of the chemokine receptors thought to have important functions in the brain is CXCR4 (Zou et al., 1998). CXCR4 has also been identified as one of co-receptors for the human immunodeficiency virus-1 (HIV-1) (Feng et al., 1996). Pretreatment with stromal cell-derived factor-la (SDF-1α/CXCL12) significantly attenuates the hypothermic effect of WIN 55,212-2, indicating that this chemokine interferes with the pathway involved in mechanisms that control the development of hypothermia induced by a cannabinoid (Benamar et al., 2009). To establish that the SDF-1α/CXCL12 effect was mediated through its receptor, the SDF-1α/CXCL12 antagonist, AMD 3100, was given directly into the POAH. In rats pretreated with AMD 3100, SDF-1α/CXCL12 is unable to alter WIN 55,212-2-induced hypothermia (Benamar et al., 2009). This finding indicates that the inhibitory effect of SDF-1α/CXCL12 on WIN 55,212-2-induced hypothermia is mediated by CXCR4. Because both chemokines and cannabinoids are found in the POAH (Herkenham et al., 1991; Mailleux and Vanderhaeghen, 1992; Moldrich and Wenger, 2000; Banisadr et al., 2003), and their receptors are members of the G protein-coupled receptor family, one likely explanation for the antagonistic effect of SDF-1α/CXCL12 on WIN 55,212-2 is interference with CB1 receptor function in the POAH through CXCR4 receptor activation. A heterologous desensitization mechanism may occur at the G protein-coupled receptor level. These data support the idea of a functional interaction between chemokine and cannabinoid systems in the brain and show that a thermoregulatory action of the cannabinoid agonist WIN 55,212-2 can be antagonized by elevated levels of SDF-1α/CXCL12.

The temptation to assume that all neurotransmitters and messengers modulate the hypothermic effect of cannabinoids and opioids should be resisted. In fact, two of our own hypotheses – that cannabinoids produce hypothermia which is dependent on a downstream increase in TRPV1 receptor signaling and vice versa (i.e., that capsaicin and other vanilloid agonists produce hypothermia which is dependent on downstream cannabinoid CB1 receptor activation) and that acetaminophen-induced hypothermia was dependent on cannabinoid CB1receptor activation were disproven (Corley and Rawls, 2009; Ding et al., 2005). Furthermore, acetaminophen-induced hypothermia was not altered by mu, kappa, or delta opioid receptor antagonists (Corley and Rawls, 2009). The ineffectiveness of opioid and cannabinoid CB1 receptor antagonists is entirely different from their effects on APAP-evoked analgesia in rats (Pini et al., 1997;Bujalska, 2004; Ottani et al., 2006). Pharmacological antagonism of mu, kappa, or delta opioid receptors inhibits acetaminophen-evoked analgesia in the paw withdrawal test and cannabinoid CB1 receptor antagonism prevents the analgesic effect of acetaminophen in the hot-plate assay (Bujalska, 2004; Ottaniet al., 2006). The interpretation from these combined results is that two of acetaminophen’s most noteworthy effects – hypothermia and analgesia – are mediated by mechanisms that are not entirely identical, with the analgesic effect dependent on the downstream activation of opioid and cannabinoid signaling pathways and the hypothermic response produced by pathways that are independent of opioid and cannabinoid receptor activation.

The authors would like to thank Dr. Martin W. Adler and Ellen Geller for their invaluable advice regarding preparation of this review article. The authors would also like to thank Jae Kim for assistance with manuscript formatting and the National Institutes of Health (DA028153, DA025314, DA022694, and DA13429) for funding some of the work discussed here.

“This is an, un-copyedited, author manuscript that has been accepted for publication in the Frontiers in Bioscience”. Cite this article as appearing in the Journal of Frontiers in Bioscience. Full citation can be found by searching the Frontiers in Bioscience (http://bioscience.org/search/authors/htm/search.htm) following publication and at PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed) following indexing. This article may not be duplicated or reproduced, other than for personal use or within the rule of “Fair Use of Copyrighted Materials” (section 107, Title 17, U.S. Code) without permission of the copyright holder, the Frontiers in Bioscience. From the time of acceptance following peer review, the full final copy edited article of this manuscript will be made available at http://www.bioscience.org/. The Frontiers in Bioscience disclaims any responsibility or liability for errors or omissions in this version of the un-copyedited manuscript or in any version derived from it by the National Institutes of Health or other parties.”

 

• Abood ME, Martin BR. Neurobiology of marijuana abuse. Trends Pharmacol. Sci. 1992;13:201–206. [PubMed]
• Adler MW. Multiple opiate receptors and their different ligand profiles.Ann. N. Y. Acad. Sci. 1982;398:340–351. [PubMed]
• Adler MW, Geller EB. Hypothermia and poikilothermia induced by a kappa-agonist opioid and a neuroleptic. Eur. J. Pharmacol.1987;140:233–237. [PubMed]
• Adler MW, Geller EB, Rosow CE, Cochin J. The opioid system and temperature regulation. Annu. Rev. Pharmacol. Toxicol. 1988;28:429–449. [PubMed]
• Adler MW, Geller EB. Physiological functions of opioids: Temperature regulation. In: Herz A, Akil H, Simon EJ, editors. Handbook of Experimental Pharmacology. Vol. 104/II. Berlin Heidelberg: Springer-Verlag; 1993. pp. 205–238. 1993. Opioids II.
• Aggarwal S, Shavalian B, Kim E, Rawls SM. Agmatine enhances cannabinoid action in the hot-plate assay of thermal nociception.Pharmacol. Biochem. Behav. 2009;93:426–432. [PubMed]
• Aghajanian GK, Kogan JH, Moghaddam B. Opiate withdrawal increases glutamate and aspartate efflux in the locus coeruleus: An in vivomicrodialysis study. Brain Res. 1994;636:126–130. [PubMed]
• Almeida MC, Branco LGS. Role of nitric oxide in insulin-induced hypothermia in rats. Brain Res. Bull. 2001;54:49–53. [PubMed]
• Anderson R, Sheehan MJ, Strong P. Characterization of the adenosine receptors mediating hypothermia in the conscious mouse. Br. J. Pharmacol. 1994;113:1386–1390. [PMC free article] [PubMed]
• Aricioglu F, Regunathan S. Agmatine attenuates stress- and lipopolysaccharide-induced fever in rats. Physiol. Behav. 2005;85:370–375. [PMC free article] [PubMed]
• Ashton JC, Glass M. The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration. Curr. Neuropharmacol.2007;5:73–80. [PMC free article] [PubMed]
• Azad SC, Marsicano G, Eberlein I, Putzke J, Zieglgansberger W, Spanagel R, Lutz B. Differential role of the NO pathway on delta(9)-THC-induced central nervous system effects in the mouse. Eur. J. Neurosci. 2001;13:561–568. [PubMed]
• Baker AK, Meert TF. Functional effects of systemically administered agonists and antagonists of mu, delta, and kappa opioid receptor subtypes on body temperature n mice. J. Pharmacol. Exp. Ther.2002;302:1253–1264. [PubMed]
• Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004;41:849–857.[PubMed]
• Banisadr G, Skrzydelski D, Kitabgi P, Rostène W, Parsadaniantz SM. Highly regionalized distribution of stromal cell-derived factor-1/CXCL12 in adult rat brain: constitutive expression in cholinergic, dopaminergic and vasopressinergic neurons. Eur. J. Neurosci.2003;18:1593–1606. [PubMed]
• Bejanian M, Pechnick RN, George R. Effects of acute and chronic administration of (+)-SKF 10,047 on body temperature in the rat: cross-sensitization with phencyclidine. J. Pharmacol. Exp. Ther.1990;253:1253–1258. [PubMed]
• Bejanian M, Pechnick RN, Bova MP, George R. Effects of subcutaneous and intracerebroventricular administration of the sigma receptor ligand 1,3-di-o-tolylguanidine on body temperature in the rat: interactions with BMY 14802 and rimcazole. J. Pharmacol. Exp. Ther. 1991;258:88–93. [PubMed]
• Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science. 1997;277:1094–1097. [PubMed]
• Beltramo M, de Fonseca FR, Navarro M, Calignano A, Gorriti MA, Grammatikopoulos G, Sadile AG, Giuffrida A, Piomelli D. Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor. J. Neurosci. 2000;20:3401–3407. [PubMed]
• Benamar K, Xin L, Geller EB, Adler MW. Blockade of lipopolysaccharide-induced fever by a μ-opioid receptor-selective antagonist in rats. Eur. J. Pharmacol. 2000;401:161–165. [PubMed]
• Benamar K, Xin L, Geller EB, Adler MW. Effect of central and peripheral administration of a nitric-oxide synthase inhibitor on morphine hyperthermia in rats. Brain Res. 2001;894:266–273.[PubMed]
• Benamar K, Geller EB, Adler MW. Role of the nitric oxide pathway in kappa-opioid-induced hypothermia in rats. J. Pharmacol. Exp. Ther.2002;303:375–378. [PubMed]
• Benamar K, Yondorf MZ, Kon D, Geller EB, Adler MW. Role of the nitric-oxide synthase isoforms during morphine-induced hyperthermia in rats. J. Pharmacol. Exp. Ther. 2003;307:219–222. [PubMed]
• Benamar K, Rawls SM, Geller EB, Adler MW. Intrahypothalamic injection of deltorphin-II alters body temperature in rats. Brain Res.2004;1019:22–27. [PubMed]
• Benamar K, McMenamin M, Geller EB, Chung YG, Pintar JE, Adler MW. Unresponsiveness of mu-opioid receptor knockout mice to lipopolysaccharide-induced fever. Br. J. Pharmacol. 2005;144:1029–1031. [PMC free article] [PubMed]
• Benamar K K, Yondorf M, Barreto VT, Geller EB, Adler MW. Deletion of mu-opioid receptor in mice alters the development of acute neuroinflammation. J. Pharmacol. Exp. Ther. 2007a;323:990–994.[PubMed]
• Benamar K, Yondorf M, Meissler JJ, Geller EB, Tallarida RJ, Eisenstein TK, Adler MW. A novel role of cannabinoids: implication in the fever induced by bacterial lipopolysaccharide. J. Pharmacol. Exp. Ther.2007b;320:1127–1133. [PubMed]
• Benamar K, Yondorf M, Geller EB, Eisenstein TK, Adler MW. Physiological evidence for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain. Br. J. Pharmacol.2009;157:1225–1231. [PMC free article] [PubMed]
• Bhargava HN, Matwyshyn GA. Dizocilpine (MK-801) blocks tolerance to the analgesic but not to the hyperthermic effect of morphine in the rat. Pharmacology. 1993;47:344–350. [PubMed]
• Bhargava HN, Thorat SN. Effect of dizocilpine (MK-801) on analgesia and tolerance induced by U-50,488H, a kappa-opioid receptor agonist, in the mouse. Brain Res. 1994;649:111–116. [PubMed]
• Bhargava HN. Non-competitive antagonism of N-methyl-D-aspartate receptor inhibits tolerance to the analgesic action of U-50,488H, a kappa-opiate receptor agonist in the rat. Gen. Pharmacol.1995;26:1055–1060. [PubMed]
• Bhargava HN, Thorat SN. Differential effects of LY235959, a competitive antagonist of the NMDA receptor on kappa-opioid receptor agonist induced responses in mice and rats. Brain Res. 1997;747:246–251. [PubMed]
• Bilsky EJ, Calderon SN, Wang T, Bernstein RN, Davis P, Hruby VJ, McNutt RW, Rothman RB, Rice KC, Porreca F. SNC 80, a selective, nonpeptidic, and systemically active opioid delta agonist. J. Pharmacol. Exp. Ther. 1995;273:359–366. [PubMed]
• Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, de Petrocellis L, di Marzo V. N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem. J. 2000;351:817–824. [PMC free article] [PubMed]
• Boulant JA, Morgane PJ, Pankesepp J, et al. Neurophysiological basis, in Behavioral Studies of the Hypothalamus. New York: Dekker; 1980. Hypothalamic control of thermoregulation; pp. 1–82.
• Bowen WD, de Costa B, Hellewell SB, Thurkauf A, Walker JM, Rice KC. Characterization of [3H] (+)-pentazocine, a highly selective sigma ligand. Prog. Clin. Biol. Res. 1990;328:117–120. [PubMed]
• Branco LG, Carnio EC, Barros RC. Role of the nitric oxide pathway in hypoxia-induced hypothermia of rats. Am. J. Physiol. 1997;273:967–971. [PubMed]
• Breder CD, Saper CB. Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res. 1996;713:64–69. [PubMed]
• Bredt DS, Snyder SH. Nitric oxide, a novel neuronal messenger.Neuron. 1992;8:3–11. [PubMed]
• Brent PJ. Similar behavioural effects of sigma agonists and PCP-like non-competitive NMDA antagonists in guinea-pigs.Psychopharmacology. 1991;105:421–427. [PubMed]
• Broccardo M, Improta G, Tabacco A. Central effect of SNC 80, a selective and systemically active delta-opioid receptor agonist, on gastrointestinal propulsion in the mouse. Eur. J. Pharmacol.1998;342:247–251. [PubMed]
• Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods JH. Nonpeptidic delta-opioid receptor agonists reduce immobility in the forced swim assay in rats. Neuropyschopharmacology. 2002;26:744–755. [PubMed]
• Brusco A, Tagliaferro PA, Saez T, Onaivi ES. Ultrastructural localization of neuronal brain CB2 cannabinoid receptors. Ann. N. Y. Acad. Sci.2008;1139:450–457. [PubMed]
• Bujalska M. Effect of nonselective and selective opioid receptors antagonists on antinociceptive action of APAP [part III] Pol. J. Pharmacol. 2004;56:539–545. [PubMed]
• Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC. Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-31 methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist. J. Med. Chem. 1994;37:2125–2128. [PubMed]
• Calignano A, La Rana G, Beltramo M, Makriyannis A, Piomelli D. Potentiation of anandamide hypotension by the transport inhibitor, AM404. Eur. J. Pharmacol. 1997;15:337, R1–R2. [PubMed]
• Calignano A, La Rana G, Giuffrida A, Piomelli D. Control of pain initiation by endogenous cannabinoids. Nature. 1998;394:277–281.[PubMed]
• Caterina MJ. Transient receptor potential ion channels as participants in thermosensation and thermoregulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007;292:64–76. [PubMed]
• Chaperon F, Thiebot MH. Behavioral effects of cannabinoid agents in animals. Crit. Rev. Neurobiol. 1999;13:243–281. [PubMed]
• Chebib M, Johnston GA. The ‘ABC’ of GABA receptors: a brief review.Clin. Exp. Pharmacol. Physiol. 1999;26:937–940. [PubMed]
• Chen WC, Huang JK, Cheng JS, Tsai JCR, Chiang AJ, Chou KJ, et al. AM-404 elevates renal intracellular Ca2+, questioning its selectivity as a pharmacological tool for investigating the anandamide transporter. J. Pharmacol. Toxicol. Methods. 2001;45:195–198. [PubMed]
• Chen X, McClatchy DB, Geller EB, Tallarida RJ, Adler MW. The dynamic relationship between mu and kappa opioid receptors in body temperature regulation. Life Sci. 2005;78:329–333. [PubMed]
• Chen XH, Geller EB, de Riel JK, Liu-Chen LY, Adler MW. Antisense oligodeoxynucleotides against mu-or kappa-opioid receptors block agonist-induced body temperature changes in rats. Brain Res.1995;688:237–241. [PubMed]
• Chen XH, Geller EB, de Riel JK, Liu-Chen LY, Adler MW. Antisense confirmation of mu- and kappa-opioid receptor mediation of morphine’s effects on body temperature in rats. Drug Alcohol Depend.1996;43:119–124. [PubMed]
• Chu K, Lee ST, Sinn DI, Ko SY, Kim EH, Kim JM, Kim SJ, Park DK, Jung KH, Song EC, Lee SK, Kim M, Roh JK. Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation.Stroke. 2007;38:177–182. [PubMed]
• Clark WG, Bernardini GL, Ponder SW. Central injection of a sigma opioid receptor agonist alters body temperature of cats. Brain Res. Bull.1981;7:279–281. [PubMed]
• Compton DR, Aceto M, Lowe J, Martin BR. In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity. J. Pharmacol. Exp. Ther. 1996;277:586–594. [PubMed]
• Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR. Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. J. Pharmacol. Exp. Ther. 1992;263:1118–1126. [PubMed]
• Contreras PC, Contreras ML, O’Donohue TL, Lair CC. Biochemical and behavioral effects of sigma and PCP ligands. Synapse. 1998;2:240–243.[PubMed]
• Corbett D, Evans S, Thomas C, Wang D, Jonas RA. MK-801 reduced cerebral ischemic injury by inducing hypothermia. Brain Res.1990;514:300–304. [PubMed]
• Corley G, Rawls SM. Opioid, cannabinoid CB1 and NOP receptors do not mediate APAP-induced hypothermia in rats. Pharmacol. Biochem. Behav. 2009;92:503–507. [PubMed]
• Costa AC, Stasko MR, Stoffel M, Scott-McKean JJ. G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. J. Neurosci. 2005;25:7801–7804. [PubMed]
• Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–87. [PubMed]
• Critchley DJ, Childs KJ, Middlefell VC, Dourish CT. Inhibition of 8-OH-DPAT-induced elevation of plasma corticotrophin by the 5-HT1A receptor antagonist WAY100635. Eur. J. Pharmacol. 1994;264:95–97.[PubMed]
• Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 2005;25:9275–9284. [PubMed]
• de Petrocellis L, Bisogno T, Davis JB, Pertwe RG, di Marzo V. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett. 2000;483:52–56. [PubMed]
• de Petrocellis L, Bisogno T, Maccarrone M, Davis JB, Finazzi-Agro A, di Marzo V. The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J. Biol. Chem. 2001;276:12856–12863.[PubMed]
• de Vry J, Jentzsch KR, Kuhl E, Eckel G. Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development. Behav. Pharmacol. 2004;15:1–12.[PubMed]
• Del Rio-Garcia J, Cremades A. GABAergic mechanisms in morphine-induced hypothermia. Eur. J. Pharmacol. 1990;187:495–500. [PubMed]
• Deutsch DG, Goligorsky MS, Schmid PC, Krebsbach RJ, Schmid HH, Das SK, Dey SK, Arreaza G, Thorup C, Stefano G, et al. Production and physiological actions of anandamide in the vasculature of the rat kidney. J. Clin. Investig. 1997;100:1538–1546. [PMC free article][PubMed]
• Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science. 1992;258:1946–1949. [PubMed]
• Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. TRPM8 is required for cold sensation in mice. Neuron. 2007;54:371–378. [PubMed]
• di Marzo V. Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci.1999;65:645–655. [PubMed]
• di Marzo V. The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol. Res. 2009;60:77–84. [PubMed]
• Ding Z, Cowan A, Rawls SM. Capsaicin evokes hypothermia independent of cannabinoid CB1 and CB2 receptors. Brain Res.2005;1065:147–51. [PubMed]
• Ding Z, Gomez T, Werkheiser JL, Cowan A, Rawls SM. Icilin induces a hyperthermia in rats that is dependent on nitric oxide production and NMDA receptor activation. Eur. J. Pharmacol. 2008;578:201–208.[PubMed]
• Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl. Acad. Sci. U. S. A.2002;99:10819–10824. [PMC free article] [PubMed]
• Dogan MD, Patel S, Rudaya AY, Steiner AA, Székely M, Romanovsky AA. Lipopolysaccharide fever is initiated via a capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor. Br. J. Pharmacol. 2004;143:1023–1032. [PMC free article] [PubMed]
• Elliott K, Minami N, Kolesnikov YA, Pasternak GW, Inturrisi CE. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain.1994;56:69–75. [PubMed]
• Eltayb A, Lindblom S, Oerther S, Ahlenius S. Additive hypothermic effects of the 5-HT1A receptor agonist 8-OH-DPAT and the dopamine D2/3 receptor agonist 7-OH-DPAT in the rat. Acta. Physiol. Scand.2001;172:205–209. [PubMed]
• Englert LF, Ho BT, Taylor D D. The effects of (−)-delta9-tetrahydrocannabinol on reserpine-induced hypothermia in rats. Br. J. Pharmacol. 1973;49:243–252. [PMC free article] [PubMed]
• Fan F, Compton DR, Ward S, Melvin L, Martin BR. Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212. J. Pharmacol. Exp. Ther. 1994;271:1383–1390. [PubMed]
• Farfel GM, Seiden LS. Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. J. Pharmacol. Exp. Ther. 1995;272:868–875.[PubMed]
• Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872–877. [PubMed]
• Fennessy MR, Taylor DA. The effect of delta9-tetrahydrocannabinol on body temperature and brain amine concentrations in the rat at differnt ambient temperatures. Br. J. Pharmacol. 1997;60:65–71.[PMC free article] [PubMed]
• Ferraro L, Tomasini MC, Gessa GL, Bebe BW, Tanganelli S, Antonelli T. The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. Cereb. Cortex. 2001;11:728–733. [PubMed]
• Fitton AG, Pertwee RG. Changes in body temperature and oxygen consumption rate of conscious mice produced by intrahypothalamic and intracerebroventricular injections of delta 9-tetahyrocannabino. Br. J. Pharmacol. 1982;75:409–414. [PMC free article] [PubMed]
• Fletcher A, Forster EA, Bill DJ, Brown G, Cliffe IA, Hartley JE, Jones DE, McLenachan A, Stanhope KJ, Critchley DJ, Childs KJ, Middlefell VC, Lanfumey L, Corradetti R, Laporte AM, Gozlan H, Hamon M, Dourish CT. Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1A receptor antagonist. Behav. Brain Res. 1996;73:337–353.[PubMed]
• Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly Y, Fletcher A. A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur. J. Pharmacol. 1995;281:81–88. [PubMed]
• Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, James I. The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain. 2001;92:91–100. [PubMed]
• Fraser GL, Parenteau H, Tu TM, Ducharme J, Perkins MN, Clarke PB. The effects of delta agonists on locomotor activity in habituated and non-habituated rats. Life Sci. 2000;67:913–922. [PubMed]
• Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 2003;83:1017–1066. [PubMed]
• García-Arencibia M, Ferraro L, Tanganelli S, Fernández-Ruiz J. Enhanced striatal glutamate release after the administration of rimonabant to 6-hydroxydopamine-lesioned rats. Neurosci. Lett.2008;438:10–13. [PubMed]
• Gavva NR, Bannon AW, Surapaneni S, Hovland DN, Jr, Lehto SG, Gore A, Juan T, Deng H, Han B, Klionsky L, Kuang R, Le A, Tamir R, Wang J, Youngblood B, Zhu D, Norman MH, Magal E, Treanor JJ, Louis JC. The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J. Neurosci. 2007;27:3366–3374.[PubMed]
• Gavva NR. Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1. Trends Pharmacol. Sci.2008:550–557. [PubMed]
• Geller EB, Hawk C, Tallarida RJ, Adler MW. Postulated thermoregulatory roles for different opiate receptors in rats. Life Sci.1982;31:2241–2244. [PubMed]
• Geller EB, Hawk C, Keinath SH, Tallarida RJ, Adler MW. Subclasses of opioids based on body temperature change in rats: acute subcutaneous administration. J. Pharmacol. Exp. Ther. 1983;225:391–398. [PubMed]
• Geller EB, Rowan CH, Adler MW. Body temperature effects of opioids in rats: intracerebroventricular administration. Pharmacol. Biochem. Behav. 1986;24:1761–1765. [PubMed]
• Gomez-Flores R, Rice KC, Zhang X, Weber RJ. Increased tumor necrosis factor-alpha and nitric oxide production by rat macrophages following in vitro stimulation and intravenous administration of the deltaopioid agonist SNC 80. Life Sci. 2001;68:2675–2684. [PubMed]
• Gourine AV. Pharmacological evidence that nitric oxide can act as an endogenous antipyretic factor in endotoxin-induced fever in rabbits.Gen. Pharmacol. 1995;26:835–841. [PubMed]
• Gullapalli S, Nemmani KV, Ramarao P. Role of Ca2+ channels on the hypothermic response produced by activation of kappa-opioid receptors. Pharmacol. Biochem. Behav. 2002;72:93–99. [PubMed]
• Gullapalli S, Ramarao P. L-type Ca2+ channel modulation by dihydropyridines potentiates kappa-opioid receptor agonist induced acute analgesia and inhibits development of tolerance in rats.Neuropharmacology. 2002;42:467–475. [PubMed]
• Gullapalli S, Ramarao P. Role of L-type Ca2+ channels in pertussis toxin induced antagonism of U50,488H analgesia and hypothermia. Brain Res. 2002;946:191–197. [PubMed]
• Gyires K. The role of endogenous nitric oxide in the gastroprotective action of morphine. Eur. J. Pharmacol. 1994;255:33–37. [PubMed]
• Hajos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106:1–4. [PubMed]
• Hajos N, Kathuria S, Dinh T, Piomelli D, Freund TF. Endocannabinoid transport tightly controls 2-arachidonoyl glycerol actions in the hippocampus: effects of low temperature and the transport inhibitor AM404. Eur. J. Neurosci. 2004;19:2991–2996. [PubMed]
• Handler CM, Geller EB, Adler MW. Effect of mu-, kappa-, and delta-selective opioid agonists on thermoregulation in the rat. Pharmacol. Biochem. Behav. 1992;43:1209–1216. [PubMed]
• Handler CM, Piliero TC, Geller EB, Adler MW. Effect of ambient temperature on the ability of mu-, kappa- and delta-selective opioid agonists to modulate thermoregulatory mechanisms in the rat. J. Pharmacol. Exp. Ther. 1994;268:847–855. [PubMed]
• Handler CM, Mondgock DJ, Zhao SF, Geller EB, Adler MW. Interaction between opioid agonists and neurotensin on thermoregulation in the rat. I. Body temperature. J. Pharmacol. Exp. Ther. 1995;274:284–292.[PubMed]
• Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. U. S. A. 2001;98:3662–3665. [PMC free article] [PubMed]
• Hayes AG, Oxford A, Reynolds M, Shingler AH, Skingle M, Smith C, Tyers MB. The effects of a series of capsaicin analogues on nociception and body temperature in the rat. Life Sci. 1984;34:1241–1248. [PubMed]
• Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, Luchessi AD, Castro LM, Giorgi R, Rioli V, Ferro ES, Devi LA. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc. Natl. Acad. Sci. U. S. A. 2007;104:20588–20593. [PMC free article][PubMed]
• Hellewell SB, Bowen WD. A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res. 1990;527:244–253. [PubMed]
• Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci.1991;11:563–583. [PubMed]
• Herling S, Coale EH, Hein DW, Winger G, Woods JH. Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon. Psychopharmacology. 1981;73:286–291.[PubMed]
• Hillard CJ, Muthian S, Kearn CS. Effects of CB(1) cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity. FEBS Lett. 1999;459:277–281. [PubMed]
• Hjorth S, Clark D, Carlsson A. Lack of functional evidence for the involvement of sigma opiate receptors in the actions of the 3-PPP enantiomers on central dopaminergic systems: discrepancies betweenin vitro and in vivo observations. Life Sci. 1985;37:673–684. [PubMed]
• Hodge J, Bow JP, Plyler KS, Vemuri VK, Wisniecki A, Salamone JD, Makriyannis A, McLaughlin PJ. The cannabinoid CB1 receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats. Behav. Brain Res. 2008;193:298–305. [PubMed]
• Holtzman SG. Phencyclidine-like discriminative effects of opioids in the rat. J. Pharmacol. Exp. Ther. 1980;214:614–619. [PubMed]
• Howlett AC. Inhibition of neuroblastoma adenylate cyclase by cannabinoid and nantradol compounds. Life Sci. 1984;35:1803–1810.[PubMed]
• Howlett AC. Pharmacology of cannabinoid receptors. Annu. Rev. Pharmacol. Toxicol. 1995;35:607–634. [PubMed]
• Huang WT, Tsai SM, Lin MT. Involvement of brain glutamate release in pyrogenic fever. Neuropharmacology. 2001;41:811–818. [PubMed]
• Itzhak Y. Modulation of the PCP/NMDA receptor complex and sigma binding sites by psychostimulants. Neurotoxicol. Teratol. 1994;16:363–368. [PubMed]
• Jackson HC, Nutt DJ. Inhibition of baclofen-induced hypothermia in mice by the novel GABAB antagonist CGP 35348. Neuropharmacology.1991;30:535–538. [PubMed]
• Jha SK, Islam F, Mallick BN. GABA exerts opposite influence on warm and cold sensitive neurons in medial preoptic area in rats. J. Neurobiol.2001;48:291–300. [PubMed]
• Jha SK, Yadav V, Mallick BN. GABA-A receptors in mPOAH simultaneously regulate sleep and body temperature in freely moving rats. Pharmacol. Biochem. Behav. 2001;70:115–121. [PubMed]
• Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, Shabon U, Bao W, Aiyar N, Yue TL, Brown AJ, Morrison AD, Douglas SA. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br. J. Pharmacol.2007;152:825–831. [PMC free article] [PubMed]
• Jonsson KO, Andersson A, Jacobsson SO, Vandevoorde S, Lambert DM, Fowler CJ. AM 404 and VDM 11 non-specifically inhibit C6 glioma cell proliferation at concentrations used to block the cellular accumulation of the endocannabinoid anandamide. Arch. Toxicol. 2003;77:201–207.[PubMed]
• Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J. Biol. Chem.1997;272:27218–27223. [PubMed]
• Kelley BG, Thayer SA. Anandamide transport inhibitor AM 404 and structurally related compounds inhibit synaptic transmission between rat hippocampal neurons in culture independent of cannabinoid CB1 receptors. Eur. J. Pharmacol. 2004;496:33–39. [PubMed]
• Kelly S, Chapman V. Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. J. Neurophysiol.2001;86:3061–3064. [PubMed]
• Kest B, Mogil JS, Sternberg WF, Pechnick RN, Liebeskind JC. Antinociception following 1,3,-di-o-tolylguanidine, a selective sigma receptor ligand. Pharmacol. Biochem. Behav. 1995;50:587–592.[PubMed]
• King M, Pan YX, Mei J, Chang A, Xu J, Pasternak GW. Enhanced kappa-opioid receptor-mediated analgesia by antisense targeting the sigma1 receptor. Eur. J. Pharmacol. 1997;331:5–6. [PubMed]
• Kinoshita H, Hasegawa T, Kameyama T, Yamamoto I, Nabeshima T. Competitive NMDA antagonists enhance the catalepsy induced by delta 9-tetrahydrocannabinol in mice. Neurosci. Lett. 1994;174:101–104.[PubMed]
• Klein TW, Newton C, Friedman H. Cannabinoid receptors and immunity. Immunol. Today. 1998;19:373–381. [PubMed]
• Knackstedt LA, Melendez RI, Kalivas PW. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol. Psychiatry. 2009 in press. [PMC free article] [PubMed]
• Kluger MJ, Kozak W, Leon LR, Soszynski D, Conn CA. 3.Cytokines and fever. Neuroimmunomodulation. 1995;2:216–223. [PubMed]
• Knapp RJ, Santoro G, de Leon IA, Lee KB, Edsall SA, Waite S, Malatynska E, Varga E, Calderon SN, Rice KC, Rothman RB, Porreca F, Roeske WR, Yamamura HI. Structure–activity relationships for SNC80 and related compounds at cloned human delta and mu opioid receptors.J. Pharmacol. Exp. Ther. 1996;277:1284–1291. [PubMed]
• Kolesnikov YA, Ferkany J, Pasternak GW. Blockade of mu and kappa 1 opioid analgesic tolerance by NPC17742, a novel NMDA antagonist. Life Sci. 1993;53:1489–1494. [PubMed]
• Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur. J. Pharmacol. 1996;296:17–22. [PubMed]
• Leker RR, Gai N, Mechoulam R, Ovadia H. Drug-Induced Hypothermia Reduces Ischemic Damage: Effects of the Cannabinoid HU-210. Stroke.2003;34:2000–2006. [PubMed]
• Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Böhme GA, Imperato A, Pedrazzini T, Roques BP, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999;283:401–404. [PubMed]
• Li G, Regunathan S, Reis DJ. Agmatine is synthesized by a mitochondrial arginine decarboxylase in rat brain. Ann. N. Y. Acad. Sci.1995;763:325–329. [PubMed]
• Lin JH, Lin MT. Nitric oxide synthase-cyclo-oxygenase pathway in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits. Br. J. Pharmacol. 1996;118:179–185. [PMC free article][PubMed]
• Lipski J, Wan CK, Bai JZ, Pi R, Li D, Donnelly D. Neuroprotective potential of ceftriaxone in in vitro models of stroke. Neuroscience.2007;146:617–629. [PubMed]
• Lopez-Figueroa MO, Day HE, Akil H, Watson SJ. Nitric oxide in the stress axis. Histol. Histopathol. 1998;13:1243–1252. [PubMed]
• Loring RH. Agmatine acts as an antagonist of neuronal nicotinic receptors. Br. J. Pharmacol. 1990;99:207–211. [PMC free article][PubMed]
• Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with brain enzyme. Proc. Natl. Acad. Sci. U. S. A. 1992;89:6711–6715. [PMC free article] [PubMed]
• Lutfy K, Doan P, Nguyen M, Weber E. Effects of ACEA-1328, a NMDA receptor/glycine site antagonist, on U50,488H-induced antinociception and tolerance. Eur. J. Pharmacol. 1999;384:1–5. [PubMed]
• Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl. Acad. Sc.i U. S. A.1992;89:3825–3829. [PMC free article] [PubMed]
• Mailleux P, Vanderhaeghen JJ. Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry.Neuroscience. 1992;48:655–668. [PubMed]
• Malberg JE, Seiden LS. Administration of fenfluramine at different ambient temperatures produces different core temperature and 5-HT neurotoxicity profiles. Brain Res. 1997;765:101–107. [PubMed]
• Malone DT, Taylor DA. Modulation of delta9-tetrahydrocannabinol-induced hypothermia by fluoxetine in the rat. Br. J. Pharmacol.1998;124:1419–1424. [PMC free article] [PubMed]
• Malone DT, Taylor DA. Involvement of somatodendritic 5-HT(1A) receptors in Delta(9)-tetrahydrocannabinol-induced hypothermia in the rat. Pharmacol. Biochem. Behav. 2001;69:595–601. [PubMed]
• Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J. Neurosci. 1987;7:2445–2464. [PubMed]
• Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H, Watson SJ. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J. Comp. Neurol. 1994;350:412–438. [PubMed]
• Marek P, Ben-Eliyahu S, Gold M, Liebeskind JC. Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat. Brain Res. 1991;547:77–81. [PubMed]
• Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther.1976;197:517–532. [PubMed]
• Martin GE, Pryzbylik AT, Spector NH. Restraint alters the effects of morphine and heroin on core temperature in the rat. Pharmacol. Biochem. Behav. 1977;7:463–469. [PubMed]
• Matsuda LA, Bonner TI, Lolait SJ. 2: Cannabinoid receptors: which cells, where, how, and why? NIDA Res. Monogr. 1992;126:48–56.[PubMed]
• Matsuno K, Matsunaga K, Senda T, Mita S. Increase in extracellular acetylcholine level by sigma ligands in rat frontal cortex. J. Pharmacol. Exp. Ther. 1993;265:851–859. [PubMed]
• McCracken KA, Bowen WD, de Costa BR, Matsumoto RR. Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity. Eur. J. Pharmacol. 1999;370:225–232.[PubMed]
• McDougal JN, Marques PR, Burks TF. Restraint alters the thermic response to morphine by postural interference. Pharmacol. Biochem. Behav. 1983;18:495–499. [PubMed]
• McGregor IS, Issakidis CN, Prior G. Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacol. Biochem. Behav.1996;53:657–664. [PubMed]
• McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation.Nature. 2002;416:52–58. [PubMed]
• Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 1995;50:83–90. [PubMed]
• Mechoulam R, Braun P, Gaoni Y. A stereospecific synthesis of (−)-delta 1- and (−)-delta 1(6)-tetrahydrocannabinols. J. Am. Chem. Soc.1967;89:4552–4554. [PubMed]
• Meller E, Chalfin M, Bohmaker K. Serotonin 5-HT1A receptor-mediated hypothermia in mice: absence of spare receptors and rapid induction of tolerance. Pharmacol. Biochem. Behav. 1992;43:405–411. [PubMed]
• Melzer N, Meuth SG, Torres-Salazar D, Bittner S, Zozulya AL, Weidenfeller C, Kotsiari A, Stangel M, Fahlke C, Wiendl H. A β-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis. PLoS ON. 2008;3:e3149. [PMC free article][PubMed]
• Mendizabal VE, Orliac ML, Adler-Graschinsky E. Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed. Eur. J. Pharmacol. 2001;427:251–262. [PubMed]
• Milanes MV, Gonzalvez ML, Fuente T, Vargas ML. Pituitary-adrenocortical response to acute and chronic administration of U-50,488H in the rat. Neuropeptides. 1991;20:95–102. [PubMed]
• Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR, Kennedy RT, Rebec GV. Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience. 2008;153:329–337. [PMC free article][PubMed]
• Miller MS, Brendel K, Buck SH, Burks TF. Dihydrocapsaicin-induced hypothermia and substance P depletion. Eur. J. Pharmacol.1982;83:289–292. [PubMed]
• Moldrich G, Wenger T. Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides. 2000;21:1735–1742. [PubMed]
• Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol. Rev. 1991;43:109–142.[PubMed]
• Nagashima T, Ohinata H, Kuroshima A. Involvement of nitric oxide in noradrenaline-induced increase in blood-flow through brown adipose tissue. Life Sci. 1994;54:17–25. [PubMed]
• Nava F, Carta G, Gessa GL. Permissive role of dopamine D(2) receptors in the hypothermia induced by delta(9)-tetrahydrocannabinol in rats.Pharmacol. Biochem. Behav. 2000;66:183–187. [PubMed]
• Nealen ML, Gold MS, Thut PD, Caterina MJ. TRPM8 mRNA is expressed in a subset of cold-responsive trigeminal neurons from rat. J. Neurophysiol. 2003;90:515–520. [PubMed]
• Nemmani KV, Gullapalli S, Ramarao P. Potentiation of kappa-opioid receptor agonist-induced analgesia and hypothermia by fluoxetine.Pharmacol. Biochem. Behav. 2001;69:189–193. [PubMed]
• Nguyen HO, Goracke-Postle CJ, Kaminski LL, Overland AC, Morgan AD, Fairbanks CA. Neuropharmacokinetic and dynamic studies of agmatine (decarboxylated arginine) Ann. N. Y. Acad. Sci.2003;1009:82–105. [PubMed]
• Nicholson RA, Liao C, Zheng J, David LS, Coyne L, Errington AC, et al. Sodium channel inhibition by anandamide and synthetic cannabimimetics in brain. Brain Res. 2003;978:194–204. [PubMed]
• Nozaki-Taguchi N, Yamamoto T. Involvement of nitric oxide in peripheral antinociception mediated by kappa- and delta-opioid receptors. Anesth. Analg. 1998;87:388–393. [PubMed]
• Okamura H, Abitbol M, Julien JF, Dumas S, Berod A, Geffard M, et al. Neurons containing messenger RNA encoding glutamate decarboxylase in rat hypothalamus demonstrated by in situ hybridization, with special emphasis on cell groups in medial preoptic area, anterior hypothalamic area and dorsomedial hypothalamic nucleus. Neuroscience.1990;39:675–699. [PubMed]
• Olmos G, DeGregorio-Rocasolano N, Paz Regalado M, Gasull T, Assumpció Boronat M, Trullas R, Villarroel A, Lerma J, García-Sevilla JA. Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor. Br. J. Pharmacol. 1999;127:1317–1326.[PMC free article] [PubMed]
• Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A. The analgesic activity of paracetamol isprevented by the blockade of cannabinoid CB1 receptors. Eur. J. Pharmacol. 2006;531:280–281. [PubMed]
• Ovadia H, Wohlman A, Mechoulam R, Weidenfeld J. Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.Neuropharmacology. 1995;34:175–180. [PubMed]
• Palazzo E, Marabese I, de Novellis V, Oliva P, Rossi F, Berrino L, Rossi F, Maione S. Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology.2001;40:319–326. [PubMed]
• Pasternak GW, Kolesnikov YA, Babey AM. Perspectives on the N-methyl-D-aspartate/nitric oxide cascade and opioid tolerance.Neuropsychopharmacology. 1995;13:309–313. [PubMed]
• Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–715.[PubMed]
• Perry KW, Fuller RW. Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci.1992;50:1683–1690. [PubMed]
• Perry KW, Fuller RW. Extracellular 5-hydroxytryptamine concentration in rat hypothalamus after administration of fluoxetine plus L-5-hydroxytryptophan. J. Pharm. Pharmacol. 1993;45:759–761. [PubMed]
• Pertwee RG. Tolerance to the effect of delta1-tetrahydrocannabinol on corticosterone levels in mouse plasma produced by repeated administration of cannabis extract or delta1-tetrahydrocannabinol. Br. J. Pharmacol. 1974;51:391–397. [PMC free article] [PubMed]
• Pertwee RG, Tavendale R. Effects of delta9-tetrahydrocannabinol on the rates of oxygen consumption of mice. Br. J. Pharmacol.1977;60:559–568. [PMC free article] [PubMed]
• Pertwee RG, Greentree SG. Delta-9-tetrahydrocannabinol-induced catalepsy in mice is enhanced by pretreatment with flurazepam or chlordiazepoxide. Neuropharmacology. 1988a;27:485–491. [PubMed]
• Pertwee RG, Greentree SG, Swift PA. Drugs which stimulate or facilitate central GABAergic transmission interact synergistically with delta-9-tetrahydrocannabinol to produce marked catalepsy in mice.Neuropharmacology. 1988b;27:1265–1270. [PubMed]
• Pertwee RG, Browne SE, Ross TM, Stretton CD. An investigation of the involvement of GABA in certain pharmacological effects of delta-9-tetrahydrocannabinol. Pharmacol. Biochem. Behav. 1991;40:581–585.[PubMed]
• Pettit DA, Harrison MP, Olson JM, Spencer RF, Cabral GA. Immunohistochemical localization of the neural cannabinoid receptor in rat brain. J. Neurosci. Res. 1998;51:391–402. [PubMed]
• Phillis BD, Ong J, White JM, Bonnielle C. Modification of -amphetamine-induced responses by baclofen in rats.Psychopharmacology. 2001;153:277–284. [PubMed]
• Picolo G, Cury Y. Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a delta- and kappa-opioid receptor agonist. Life Sci.2004;75:559–573. [PubMed]
• Piletz JE, Chikkala DN, Ernsberger P. Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha-2 adrenergic receptors. J. Pharmacol. Exp. Ther.1995;272:581–587. [PubMed]
• Pini LA, Vitale G, Ottani A, Sandrini M. Naloxone-reversible antinociception by paracetamolin the rat. J. Pharmacol. Exp. Ther.1997;280:934–940. [PubMed]
• Pintor A, Tebano MT, Martire A, Grieco R, Galluzzo M, Scattoni ML, Pèzzola A, Coccurello R, Felici F, Cuomo V, Piomelli D, Calamandrei G, Popoli P. The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum.Neuropharmacology. 2006;51:1004–1012. [PubMed]
• Pohorecky LA, Skiandos A, Zhang X, Rice KC, Benjamin D. Effect of chronic social stress on delta-opioid receptor function in the rat. J. Pharmacol. Exp. Ther. 1999;290:196–206. [PubMed]
• Popik P, Skolnick P. The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence. Pharmacol. Biochem. Behav. 1996;53:791–797. [PubMed]
• Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C. Nature. 2000;408:985–990. [PubMed]
• Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, Su TP, Tam SW, Taylor DP. A proposal for the classification of sigma binding sites. Trends Pharmacol. Sci. 1992;13:85–86. [PubMed]
• Rawls SM, Cabassa J, Geller EB, Adler MW. CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia. J. Pharmacol. Exp. Ther. 2002a;301:963–968. [PubMed]
• Rawls SM, Baron DA, Geller EB, Adler MW. Sigma sites mediate DTG-evoked hypothermia in rats. Pharmacol. Biochem. Behav.2002b;73:779–786. [PubMed]
• Rawls SM, Cowan A, Tallarida RJ, Geller EB, Adler MW. N-methyl-D-aspartate antagonists and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one], a cannabinoid agonist, interact to produce synergistic hypothermia. J. Pharmacol. Exp. Ther. 2002c;303:395–402.[PubMed]
• Rawls SM, Adler MW, Gaughan JP, Baron A, Geller EB, Cowan A. NMDA receptors modulate morphine-induced hyperthermia. Brain Res.2003;984:76–83. [PubMed]
• Rawls SM, Tallarida RJ, Gray AM, Geller EB, Adler MW. L-NAME (N omega-nitro-L-arginine methyl ester), a nitric-oxide synthase inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H pyrrolo[3,2,1ij]quinolin-6-one], a cannabinoid agonist, interact to evoke synergistic hypothermia. J. Pharmacol. Exp. Ther. 2004a;308:780–786. [PubMed]
• Rawls SM, Tallarida RJ, Kon DA, Geller EB, Adler MW. GABAA receptors modulate cannabinoid-evoked hypothermia. Pharmacol. Biochem. Behav. 2004b;78:83–91. [PubMed]
• Rawls SM, Hewson JM, Inan S, Cowan A. Brain delta2 opioid receptors mediate SNC-80-evoked hypothermia in rats. Brain Res.2005a;1049:61–69. [PubMed]
• Rawls SM, Ding Z, Gray AM, Cowan A. Peripheral kappa-opioid agonist, ICI 204448, evokes hypothermia in cold-exposed rats. Pharmacology.2005b;74:79–83. [PubMed]
• Rawls SM, Cowan A. Modulation of delta opioid-evoked hypothermia in rats by WAY 100635 and fluoxetine. Neurosci. Lett. 2006a;398:319–324. [PubMed]
• Rawls SM, Allebach C, Cowan A. Nitric oxide synthase mediates delta opioid receptor-induced hypothermia in rats. Eur. J. Pharmacol.2006b;536:109–112. [PubMed]
• Rawls SM, Ding Z, Cowan A. Role of TRPV1 and cannabinoid CB1 receptors in AM 404-evoked hypothermia in rats. Pharmacol. Biochem. Behav. 2006c;83:508–516. [PubMed]
• Rawls SM, Tallarida RJ, Zisk J. Agmatine and a cannabinoid agonist, WIN 55212-2, interact to produce a hypothermic synergy. Eur. J. Pharmacol. 2006d;553:89–98. [PubMed]
• Rawls SM, Tallarida R, Robinson W, Amin M. The beta-lactam antibiotic, ceftriaxone, attenuates morphine-evoked hyperthermia in rats. Br. J. Pharmacol. 2007a;151:1095–1102. [PMC free article][PubMed]
• Rawls SM, Schroeder JA, Ding Z, Rodriguez T, Zaveri N. NOP receptor antagonist, JTC-801, blocks cannabinoid-evoked hypothermia in rats.Neuropeptides. 2007b;41:239–247. [PubMed]
• Rawls SM, Robinson W, Patel S, Baron A. Beta-lactam antibiotic prevents tolerance to the hypothermic effect of a kappa opioid receptor agonist. Neuropharmacology. 2008;55:865–870. [PubMed]
• Rawls SM, Patel H, Zielinski M, Sacavage S, Baron DA, Patel D. Beta-lactam antibiotic reduces morphine analgesic tolerance in rats through GLT-1 transporter activation. Drug Alcohol. Depend. 2010a;107:261–263. [PMC free article] [PubMed]
• Rawls SM, Baron DA, Kim JK. β-lactam antibiotic inhibits development of morphine physical dependence in rats. Behav. Pharmacol.2010b;21:161–164. [PMC free article] [PubMed]
• Reid G, Babes A, Pluteanu F. A cold and menthol-activated current in rat dorsal root ganglion neurons, properties and role in cold transduction. J. Physiol. 2002;545:596–614. [PMC free article][PubMed]
• Reid G, Flonta ML. Ion channels activated by cold and menthol in cultured rat dorsal root ganglion neurons. Neurosci. Lett.2002;324:164–168. [PubMed]
• Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain?Trends Pharmacol. Sci. 2000;21:187–193. [PubMed]
• Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Cogny C, Martinez S, Maruani J, Néliat G, Caput D. SR141617A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett.1994;350:240–244. [PubMed]
• Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, Oustric D, Sarran M, Bouaboula M, Calandra B. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 1998;284:644–650. [PubMed]
• Romero J, Wenger T, de Miguel R, Ramos JA, Fernández-Ruiz JJ. Cannabinoid receptor binding did not vary in several hypothalamic nuclei after hypothalamic deafferentation. Life Sci. 1998;63:351–356.[PubMed]
• Ross RA, Gibson TM, Brockie HC, Leslie M, Pashmi G, Craib SJ, et al. Structure–activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br. J. Pharmacol. 2001;13:631–640.[PMC free article] [PubMed]
• Roth J, Störr B, Voigt K, Zeisberger E. Inhibition of nitric oxide synthase results in a suppression of interleukin-1-induced fever in rats.Life Sci. 1998;62:PL345–PL350. [PubMed]
• Roth J, Storr B, Voigt K, Zeisberger E. Inhibition of nitric oxide synthase attenuates lipopolysaccharide-induced fever without reduction of circulating cytokines in guinea-pigs. Pflueg. Arch. 1998;436:858–862. [PubMed]
• Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433:73–77. [PubMed]
• Ruskin DN, Anand R, Lahoste GJ. Menthol and nicotine oppositely modulate body temperature in the rat. Eur. J. Pharmacol.2007;559:161–164. [PubMed]
• Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol.2007;152:1092–1101. [PMC free article] [PubMed]
• Salmi P, Kela J, Arvidsson U, Wahlestedt C. Functional interactions between delta- and mu-opioid receptors in rat thermoregulation. Eur. J. Pharmacol. 2003;458:101–106. [PubMed]
• Sancibrian M, Serrano JS, Minano FJ. Opioid and prostaglandin mechanisms involved in the effects of GABAergic drugs on body temperature. Gen. Pharmacol. 1991;22:259–262. [PubMed]
• Sari Y, Smith KD, Ali PK, Rebec GV. Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J. Neurosci. 2009;29:9239–9243. [PMC free article] [PubMed]
• Sastre M, Regunathan S, Galea E, Reis DJ. Agmatinase activity in rat brain: a metabolic pathway for the degradation of agmatine. J. Neurochem. 1996;67:1761–1765. [PubMed]
• Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, George SR, O’Dowd BF. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res. Mol. Brain Res. 1999;64:193–198. [PubMed]
• Scammell TE, Elmquist JK, Saper CB. Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever.Am. J. Physiol. 1996;271:R333–R338. [PubMed]
• Schmeling WT, Hosko MJ. Hypothermic effects of intraventricular and intravenous administration of cannabinoids in intact and brainstem transected cats. Neuropharmacology. 1980;19:567–573. [PubMed]
• Shen M, Piser TM, Seybold VS, Thayer SA. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J. Neurosci. 1996;16:4322–4334. [PubMed]
• Shukla VK, Turndorf H, Bansinath M. Pertussis and cholera toxins modulate kappa-opioid receptor agonists-induced hypothermia and gut inhibition. Eur. J. Pharmacol. 1995;16(292):293–299. [PubMed]
• Sieghart W, Fuchs K, Zezula J, Buchstaller A, Zimprich F, Lassmann H. Biochemical, immunological, and pharmacological characterization of GABAA-benzodiazepine receptor subtypes. Adv. Biochem. Psychopharmacol. 1992;47:155–162. [PubMed]
• Singh J, Gupta MC. Effect of aspartate and glutamate on nociception, catalepsy and core temperature in rats. Indian J. Physiol. Pharmacol.1997;41:123–128. [PubMed]
• Sink KS, Vemuri VK, Wood J, Makriyannis A, Salamone JD. Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113. Pharmacol. Biochem. Behav. 2009;91:303–306. [PMC free article] [PubMed]
• Spencer RL, Hruby VJ, Burks TF. Body temperature response profiles for selective mu, delta and kappa opioid agonists in restrained and unrestrained rats. J. Pharmacol. Exp Ther. 1988;246:92–101. [PubMed]
• Spina E, Trovati A, Parolaro D, Giagnoni G. A role of nitric oxide in WIN 55,212-2 tolerance in mice. Eur. J. Pharmacol. 1998;343:157–163.[PubMed]
• Stefano GB, Bilfinger TV, Rialas CM, Deutsch DG. 2-arachidonyl-glycerol stimulates nitric oxide release from human immune and vascular tissues and invertebrate immunocytes by cannabinoid receptor 1. Pharmacol. Res. 2000;42:317–322. [PubMed]
• Stefano GB, Salzet B, Rialas CM, Pope M, Kustka A, Neenan K, Pryor S, Salzet M. Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. Brain Res.1997;763:63–68. [PubMed]
• Steiner AA, Carnio EC, Antunes-Rodrigues J, Branco LG. Role of nitric oxide in systemic vasopressin-induced hypothermia. Am. J. Physiol.1998;275:R937–R941. [PubMed]
• Steinfels GF, Tam SW, Cook L. Electrophysiological effects of selective sigma-receptor agonists, antagonists, and the selective phencyclidine receptor agonist MK-801 on midbrain dopamine neurons.Neuropsychopharmacology. 1989;2:201–208. [PubMed]
• Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell.2003;112:819–829. [PubMed]
• Su RB, Li J, Qin BY. A biphasic opioid function modulator: agmatine.Acta Pharmacol Sin. 2003;24:631–636. [PubMed]
• Sugiura T, Waku K. 2-Arachidonoylglycerol and the cannabinoid receptors. Chem. Phys. Lipids. 2000;108:89–106. [PubMed]
• Tallarida RJ. Drug synergism: its detection and applications. J. Pharmacol. Exp. Ther. 2001;298:865–872. [PubMed]
• Tam SW, Steinfels GF, Gilligan PJ, Schmidt WK, Cook L. DuP 734 [1-(cyclopropylmethyl)-4-(2′(4″-fluorophenyl)-2′-oxoethyl)-piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles. J. Pharmacol. Exp. Ther. 1992;263:1167–1174. [PubMed]
• Tao R, Auerbach SB. Opioid receptor subtypes differentially modulate serotonin efflux in the rat central nervous system. J. Pharmacol. Exp. Ther. 2002;303:549–556. [PubMed]
• Taylor WF, Bishop VS. A role for nitric oxide in active thermoregulatory vasodilation. Am. J. Physiol. 1993;264:H1355–H1359. [PubMed]
• Thut PD, Wrigley D, Gold MS. Cold transduction in rat trigeminal ganglia neurons in vitro. Neuroscience. 2003;119:1071–1083. [PubMed]
• Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991;251:85–87.[PubMed]
• Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998;83:393–411. [PubMed]
• van der Stelt M, di Marzo V. The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur. J. Pharmacol.2003;480:133–150. [PubMed]
• van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors.Science. 2005;310:329–332. [PubMed]
• Varga A, Németh J, Szabó A, McDougall J, Zhang C, Elekes K, Pintér E, Szolcsányi J, Helyes Z. Effects of the novel TRPV1 receptor antagonist SB366791 in vitro and in vivo in the rat. Neurosci. Lett. 2005;385:137–142. [PubMed]
• von Voigtlander PF, Lewis RA. U-50,488, a selective kappa opioid agonist: comparison to other reputed kappa agonists. Prog. Neuropsychopharmacol. Biol. Psychiatry. 1982;6:467–470. [PubMed]
• Wallenstein MC. Role of adrenal medulla in morphine-induced hyperthermia through central action. Br. J. Pharmacol. 1982;76:565–568. [PMC free article] [PubMed]
• Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY. 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A. J. Pharmacol. Exp. Ther. 2008;324:1073–1083. [PMC free article][PubMed]
• Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JF. 1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs. Proc. Natl. Acad. Sci. U. S. A. 1986;83:8784–8788. [PMC free article][PubMed]
• Wei ET. Chemical stimulants of shaking behaviour. J. Pharm. Pharmacol. 1976;28:722–723. [PubMed]
• Wei ET, Seid DA. AG-3–5: a chemical producing sensations of cold. J. Pharm. Pharmacol. 1983;35:110–112. [PubMed]
• Welch SP, Huffman JW, Lowe J. Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A. J. Pharmacol. Exp. Ther. 1998;286:1301–1308. [PubMed]
• Werkheiser JL, Rawls SM, Cowan A. Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats. Eur. J. Pharmacol. 2006;547:101–105. [PubMed]
• Werkheiser JL, Rawls SM, Cowan A. Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum. Neuropharmacology.2007;52:925–930. [PMC free article] [PubMed]
• Wickman K, Karschin C, Karschin A, Picciotto MR, Clapham DE. Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. J. Neurosci. 2000;20:5608–5615. [PubMed]
• Wiley JL, Barrett RL, Lowe J, Balster RL, Martin BR. Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats. Neuropharmacology. 1995;34:669–676. [PubMed]
• Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.Brain Res. Rev. 2009;60:267–277. [PubMed]
• Woods JH, Koek W, Weber E. Behavioral similarities of di-tolylguanidine (DTG), a selective ligand for haloperidol-sensitive sigma binding sites, to phencyclidine (PCP), in rats, pigeons, rhesus monkeys.Fed. Proc. 1987;46:951.
• Xin L, Geller EB, Adler MW. Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain. J. Pharmacol. Exp. Ther. 1997;281:499–507. [PubMed]
• Yakimova K, Ovtcharov R. Central temperature effects of the transmitter amino acids. Acta. Physiol. Pharmacol. Bulg. 1989;15:50–54. [PubMed]
• Yamada M, Inanobe A, Kurachi Y. G protein regulation of potassium ion channels. Pharmacol. Rev. 1998;50:723–760. [PubMed]
• Yang XC, Reis DJ. Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J. Pharmacol. Exp. Ther. 1999;288:544–549. [PubMed]
• Zarrindast MR, Oveissi Y. GABAA and GABAB receptor sites involvement in rat thermoregulation. Gen. Pharmacol. 1988;19:223–226. [PubMed]
• Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI. Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. U. S. A. 1999;96:5780–5785. [PMC free article] [PubMed]
• Zukin SR, Brady KT, Slifer BL, Balster RL. Behavioral and biochemical stereoselectivity of sigma opiate/PCP receptors. Brain Res.1984;294:174–177. [PubMed]
• Zygmunt PM, Chuang HH, Movahed P, Julius D, Högestätt ED. The anandamide transport inhibitor AM404 activates vanilloid receptors.Eur. J. Pharmacol. 2000;396:39–42. [PubMed]