Themed Section: Endocannabinoids
EDITORIAL
Correspondence
Cherry LWainwright, Centre for Cardiometabolic Health Res earch, Faculty of Health and Social Care, Sir Ian Wood Building, Garthdee Road, Aberdeen, AB10 7GJ, UK. E-mail: c.wainwright@rgu.ac.uk
Cherry LWainwright
Centre for Car diom etabol ic Heal th Resear ch, Rob ert Gordo n University, Aberdeen, UK
LINKED ARTICLES
This article is part of a themed section on Endocannabinoids. To view t he other ar ticles in this secti on visit http://onlinelibrary.
wiley.com/doi/10.1111/bph.v173.7/issuetoc.
Research carried out in the 1940s gave some of our first inklings of the pharmacological potential of chemicals extracted from Cannabis sativa (Loewe and Adams, 1947), but it was not until the early 1960s that Δ9tetrahyrocannabinol (Δ9-THC) was shown to be one of the major constituents of cannabis that induces behavioural and psychoactive changes (Boyd et al.,1963). The next 30 years led to intensive research around the pharmacology of Δ9-THC and other related plant derived cannabinoids that, over time, led to the discovery and subsequent identification in the early 1990s of (i) G-protein coupled CB1 (Matsuda et al., 1990) and CB2 (Munro et al., 1993) cannabinoid receptors; (ii) endogenous CB receptor ligands, of which N–arachidonoyl-ethanolamine (anandamide, AEA; Devane et al., 1992) and 2-arachidonyl glycerol (2-AG; Mechoulam et al.,1995) represent the most intensively studied; and (iii) the associated enzymatic apparatus that controls their synthesis and degradation (recently reviewed by Cascio and Marini, 2015). Taken together, these three components were subsequently described as the endocannabinoid system (ECS), which has since been shown to comprise an endogenous signalling system that plays a pivotal role in a variety of centrally and peripherally regulated physiological processes, including pain sensation, appetite, memory, mood and inflammation, and in the pathophysiology of numerous disease states, including cancer, diabetes, obesity and cardiovascular disease. To date, in excess of 7000 original articles and reviews have been published (>300 in the British Journal of Pharmacology) that have helped advance our knowledge about this complex and intriguing system. In this themed issue of the BJP, a further review and three original papers add additional insight and understanding of the role of the ECS in diabetes (and its complications; Gruden et al., 2016), obesity-related nephropathy (Jenkin et al.,2016) and drug withdrawal (Wang et al., 2016). Additionally, the paper of Petrosino et al. (2016) describes the intricate interaction between various elements of the ECS and their cellular targets.
Type 2 diabetes has been described as a pandemic, and the global incidence is persistently on the rise because of the growing levels of obesity. The catastrophic consequences that follow the development of this condition, in the form of complications such as diabetic retinopathy, nephropathy, neuropathy and cardiovascular disease, only serve to heighten the need for effective treatments to both prevent and manage the disease. The ECS has been known for some time to play an important regulatory central role in food intake; however, it is only in the last 10–15 years that we have come to appreciate an equally important role in peripheral tissues that contribute to energy metabolism and homeostasis, such as adipose tissue and pancreatic islets (reviewed by Silvestri and Di Marzo, 2013). In this themed issue of the BJP, an excellent review from Pal Pacher’s group provides an update on the role of the ECS in obesity and insulin resistance, alongside a detailed description of how the peripheral ECS is important in the pathogenesis of diabetic nephropathy, neuropathy and cardiomyopathy (Gruden et al., 2016). In this review, they highlight the opposing effects of the two cannabinoid (CB1 and CB2) receptors in various cellular events implicated in the development of diabetic complications, including inflammation and oxidative stress, where activation of CB2 or blockade of CB1 receptors both present potential opportunities for drug development in the treatment of diabetic complications. However, the review also emphasises the challenges faced in terms of the selectivity of agents for each of the CB receptors and their centrally mediated adverse effects, the latter requiring the development of peripherally restricted cannabinoid-based therapies. Of particular interest is the apparent association between a common polymorphism in the CB1 receptor and the occurrence of nephropathy and retinopathy in people with type 2 diabetes; although the functional importance of these remains to be demonstrated, this may provide a promising approach to the management of complications of this disorder.
Aligning well with the above review, also within this issue is an original contribution from Jenkin et al. (2016) that focuses on the role of CB2receptors in obesity-induced renal dysfunction. Using a high fat diet-induced rat model of obesity, they studied the effects of both activation (with AM1241) and blockade (with AM630) of the CB2 receptor. While neither compound influenced weight gain, AM1241 markedly improved a number of renal function markers, while AM630 led to a worsening of the renal dysfunction, adding to the existing body of evidence that CB2 receptor activation may be of benefit in obesity-related nephropathy. However, as noted in Gruden’s review, the potential adverse effects on insulin resistance that have been reported following CB2 receptor activation, albeit with a different CB2 agonist (JH-133; Deveaux et al., 2009), underline the need for the development of ligands that are highly selective for the CB receptor target.
Inflammation is one of the key events that contribute to the development of diabetic complications. To date, the focus on the role of the ECS in the inflammatory process has been on the two most studied endocannabinoids AEA and 2-AG. In the paper by Petrosino et al. (2016), we are reminded that other products of the same synthetic pathways that give rise to AEA play an important role in endocannabinoid signalling. Palmitoylethanolamide (PEA) is an AEA congener that is synthesised alongside AEA, and various reports from the literature show that it can modulate the action of AEA at both CB receptors. Moreover, this article similarly reminds us that AEA has actions not only at the GPCRs but also at other cellular targets, including TRPV1, while, on the other hand, 2-AG is relatively inactive at the CB receptors yet a ‘physiologically relevant’ activator of TRPV1. Here, Petrosino et al. describe studies to demonstrate that, while PEA itself has very low affinity for both CB receptors and TRPV1, it appears to play an important role in modulating the activity of 2-AG at this receptor (so-called pleiotropic effects). Using a combined in vivo and in vitro approach, PEA was found to elevate 2-AG levels in cultured keratinocytes and to raise plasma levels of 2-AG following oral administration in both humans and dogs. However, at the cellular level, PEA only slightly augmented the activation of TRPV1 by 2-AG while increasing the 2-AG-induced desensitisation of TRPV1 to capsaicin. Through these experiments, the authors have extended the previously described ‘entourage effect’ of PEA on AEA signalling (De Petrocellis et al., 2001) to that for 2-AG, providing a plausible explanation for why antagonists of both CB receptors and TRPV1 attenuate responses to PEA.
Moving away from the topic of diabetes and obesity, the final paper in this themed issue tackles the subject of the involvement of the ECS in pathways that regulate drug addiction. CB1 receptors are highly expressed in regions of the brain linked with reward and drug addiction, and CB1 receptor activation has been shown to reinstate drug-seeking behaviour, while CB1 receptor blockade has the opposite effect. Previous evidence has suggested that synaptic plasticity occurs as both a short- and long-term event in various areas of the brain associated with drug reward and addiction. Wang et al. (2016) have studied the role of the ECS in synaptic plasticity within the nucleus accumbens, where they have provided important evidence to show that the modulation of inhibitory synaptic transmission by endocannabinoids is magnified following short-term morphine withdrawal in rats. In the case of 2-AG, but not AEA, this was associated with an increased expression, of diacylglycerol lipase α (DAGLα), which is the enzyme responsible for 2-AG synthesis. Although the precise mechanism underlying this remains to be identified, the findings of this study emphasise once more not only the complexity of the roles that the ECS plays in physiology (and pathophysiology) but also that the ECS is under exquisite control by both itself and other systems.
Despite the growing understanding of the ECS, one theme that emerges from all of the papers in this issue is that we need to know more about how the ECS works in order to be able to develop novel drugs targeting this system. In particular, we need to understand how the ECS ‘self-regulates’, so that, when one pathway or receptor is blocked, we avoid activating a different pathway that would either negate what we are trying to achieve or trigger adverse effects. Although advances are being made in the development of novel agents targeting only peripheral CB1 receptors (to avoid the adverse psychiatric effects seen with centrally acting CB1 antagonists), we still need to be cautious about how blockade of these receptors may affect the fine balance within the ECS that is helping to maintain physiological control, particularly in body systems that are unrelated to the target system. Drug selectivity is also key, because very few cannabinoid ligands (acting as either agonists or antagonists) appear to be completely selective for one receptor, reflecting in a way the promiscuity of the endogenous cannabinoid ligands themselves. Finally, the behaviour of cannabinoid ligands at different receptors may vary depending upon whether or not they are being studied in cell systems, tissue preparations or in vivo; indeed, at least in terms of haemodynamic responses, recent data show that the receptor activity profile of ‘selective’ cannabinoid ligands can vary between in vitro and in vivo model systems (Walsh et al., 2015), which may reflect an involvement of the ECS and receptor crosstalk in intact animals that is not observed in isolated cells. There is, therefore, a strong possibility that such discrepancies may also be seen in other physiological systems.
References
- , , , (1963). Effects of tetrahydrocannabinols and other drugs on operant behaviour in rats. Arch Int Pharmacodyn Ther 144: 533–554.
- , (2015). biosynthesis and fate of endocannabinoids. Handb Exp Pharmacol 231: 39–58.
- , , (2001). Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett 506: 253–256.
Direct Link:
- , , , , , , et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258: 1946–1949.
- , , , , , , et al. (2009). Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One 4: e5844.
- , , , (2016). Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol 173: 1116–1127.
- , , , , , , et al. (2016). Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity. Br J Pharmacol 173: 1128–1142.
- , (1947). Structure–activity relationship (SAR) and pharmacological peculiarities of new synthetic congeners of tetrahydrocannabinol. Fed Proc 6: 352.
- , , , , (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346: 561–564.
- , , , , , (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. BiochemPharmacol 50: 83–90.
- , , (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature 365: 61–65.
- , , , , , , (2016). The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol 173: 1154–1162.
- , (2013). The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 17: 475–490.
- , , , , , , et al. (2015). Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach. Pharmacol Res Perspect 3 e00143.
Direct Link:
- , , , , , , et al. (2016). The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-α expression following short-term morphine withdrawal. Br J Pharmacol 173: 1143–1153.
BJP
DO I:10.1111/bph.13451© 2016 The B ritish Pharmacolo gical Society
