Volume 103, Issue 3, January 2013, Pages 444–449
The periaqueductal gray contributes to bidirectional enhancement of antinociception between morphine and cannabinoids
- Department of Psychology, Washington State University Vancouver, 14204 NE Salmon Creek Ave., Vancouver, WA 98686-9600, USA
Abstract
Co-administration of opioids and cannabinoids can enhance pain relief even when administered on different days. Repeated systemic administration of morphine has been shown to enhance the antinociceptive effect of tetrahydrocannabinol (THC) administered 12 h later, and repeated microinjection of the cannabinoid receptor agonist HU-210 into the ventrolateral periaqueductal gray (PAG) has been shown to enhance the antinociceptive effect of morphine administered 1 day later. The primary objective of the present study was to test the hypothesis that this cannabinoid/opioid interaction is bidirectional. Experiment 1 showed that microinjection of morphine into the ventrolateral PAG of male Sprague–Dawley rats twice daily for 2 days enhanced the antinociceptive effect of HU-210 measured 1 day later. In Experiment 2, twice daily systemic injections of THC enhanced the antinociceptive effect of morphine administered 1 day later. These results complement the previously mentioned studies by showing that morphine and cannabinoid interactions are bidirectional and that the ventrolateral PAG plays an important role in this effect. In contrast to the PAG, repeated administration of HU-210 or the cannabinoid receptor agonist, WIN 55,212-2, into the RVM had a neurotoxic effect. Rats became ill following repeated cannabinoid administration whether given alone or with morphine. Presumably, this neurotoxic effect was caused by the high cannabinoid concentration following RVM microinjection because rats did not become ill following repeated systemic THC administration. These findings indicate that alternating opioid and cannabinoid treatment could produce a longer lasting and more potent analgesia than either compound given alone.
Highlights
Abbreviations
- PAG, periaqueductal gray;
- RVM, rostral ventromedial medulla;
- MPE, maximal possible effect;
- CB,cannabinoid
Keywords
- Cannabinoid;
- Opioid;
- Periaqueductal gray;
- Rostral ventromedial medulla;
- Analgesia;
- Morphine
Figures and tables from this article:
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Fig. 1.
Location of microinjection sites in and immediately adjacent to the ventrolateral PAG. There is no difference in the location of microinjection sites for rats pretreated with saline (□) or morphine (■). Injection sites are plotted on coronal sections of the midbrain anterior to the interaural line (Paxinos and Watson, 2005).
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Fig. 2.
Enhanced cannabinoid antinociception in the PAG of morphine tolerant rats. Microinjection of the CB1 receptor agonist HU-210 into the PAG produced minimal antinociception in vehicle-pretreated rats, but significantly greater antinociception in rats pretreated with morphine into the PAG twice a day for 2 days (*p < 0.05). Cumulative doses of HU-210 were administered 1 day after the last morphine injection.
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Fig. 3.
Enhanced morphine antinociception following repeated systemic administration of THC. Administration of cumulative doses of morphine caused a dose-dependent increase in hot plate latency in both pretreatment groups. However, morphine potency was enhanced in THC pretreated rats even though morphine was injected 16 h after the last of four THC injections.
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Fig. 4.
Hot plate latency following an acute microinjection of a CB1 receptor agonist and/or morphine into the RVM. Microinjection into the RVM of CB1 receptor agonists (HU-210 or WIN 55,212-2) combined with morphine caused an antinociceptive effect that was greater than administration of either drug alone (*p = 0.05). Rats that became sick with repeated injections were not included in this analysis so as not to confound neurotoxic and receptor mediated effects.
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Table 1.Number of rats removed from study because of illness.
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Table 2.Enhanced antinociception between opioids and cannabinoids is bidirectional.
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- Corresponding author at: 14204 NE Salmon Creek Ave., Vancouver, WA 98686-9600, USA. Tel.: + 1 360 546 9726; fax: + 1 360 546 9038.
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- Present address: Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St. Leonards, NSW, Australia.
Copyright © 2012 Elsevier Inc. All rights reserved.
