Interactions between Δ9-tetrahydrocannabinol and μ opioid receptor agonists in rhesus monkeys: discrimination and antinociception

Abstract

Rationale-Opioid receptor agonists can enhance some effects of cannabinoid receptor agonists and cannabinoid receptor agonists can enhance some effects of opioid receptor agonists; however, the generality of these interactions is not established.Objective-This study examined interactions between the discriminative stimulus and antinociceptive effects of μ opioid receptor agonists and Δ 9 -tetrahydrocannabinol (THC) in rhesus monkeys.Results-Neither heroin nor morphine (i.v. or s.c.) altered the discriminative stimulus effects of THC in monkeys (n=5) discriminating 0.1 mg/kg THC i.v. In contrast, THC (s.c.) markedly attenuated the discriminative stimulus effect of morphine and heroin in non-dependent monkeys (n=4) discriminating 1.78 mg/kg morphine s.c. Doses of THC that attenuated the discriminative stimulus effects of morphine in non-dependent monkeys failed to modify the discriminative stimulus effects of morphine in morphine-dependent (5.6 mg/kg/12 hr) monkeys (n=4) discriminating 0.0178 mg/kg naltrexone s.c. THC also failed to modify the discriminative stimulus effects of naltrexone in morphine-dependent monkeys or the effects of midazolam in monkeys (n=4) discriminating 0.32 mg/kg midazolam s.c. Doses of THC (s.c.) that attenuated the discriminative stimulus effects of morphine in non-dependent monkeys enhanced the antinociceptive effects of morphine (s.c.) in non-dependent monkeys. While μ receptor agonists did not alter the discriminative stimulus effects of THC, in a context-dependent manner THC altered the effects of μ receptor agonists.Conclusion-That the same doses of THC enhance, attenuate, or do not affect morphine, depending on the condition, suggests that attenuation of morphine by THC can result from perceptual masking rather than common pharmacodynamic mechanisms or pharmacokinetic interactions. Keywordsopioid; THC; drug discrimination; rhesus monkey; perceptual masking; morphine; heroin; midazolam; naltrexone; antinociception Cannabinoid receptor agonists and μ opioid receptor agonists have some effects in common (e.g. antinociception): drugs from both classes have important therapeutic effects and some are abused (e.g., marijuana and heroin). Cannabinoid and opioid systems and drugs interact under a broad range of conditions, from cellular (Rios et al. 2006) to behavioral (e.g. Haney NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2012 October 24.Published in final edited form as:Psychopharmacology (Berl). 2008 August ; 199(2): 199-208. doi:10.1007/s00213-008-1157-0. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript2007) measures of drug action. Understanding these interactions could be especially important for developing novel medications that might comprise both cannabinoid and opioid mechanisms and for understanding the factors that contribute to polydrug abuse.Especially relevant to polydrug abuse are studies on the combined effects of opioids and cannabinoids on behavioral measures that are related to and p...

Interactions betweenμ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

“…These studies extend previous research (Li et al, 2008(Li et al, , 2012 by examining interactions of opioids with two cannabinoid receptor agonists, 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and WIN 55,212, which have overlapping but not identical pharmacology (e.g., greater efficacy at cannabinoid receptors) (Breivogel and Childers, 2000), compared with D 9 -THC. Moreover, the current experiment investigated the mechanism(s) underlying such interactions by assessing the ability of the cannabinoid receptor antagonist rimonabant to attenuate the effects of CP 55,940 and WIN 55,212 on morphine discrimination and heroin selfadministration.…”

“…-THC fails to enhance and can attenuate the discriminative stimulus effects of morphine and heroin (Li et al, 2008). Moreover, acute administration of D…”

“…-THC and other cannabinoid receptor agonists [e.g., (R)-(1)- [2, pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212)] have antinociceptive effects when administered alone (Vivian et al, 1998;Ko and Woods, 1999;Manning et al, 2001), and acute administration of D 9 -THC enhances the antinociceptive effects of morphine (Li et al, 2008).…”

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

“…-HU-210 and the non-steroidal anti-inflammatory drug, acetylsalicylic acid, co-administered systemically, in the rat hot plate model of acute pain [76]; -D 9 -THC and an opioid such as morphine, codeine or fentanyl in mouse, rat, guinea pig and monkey models of acute or arthritic pain [79][80][81][82][83][84][85][86][87][88][89]; -CP55940 and the a 2 -adrenoceptor agonist, dexmedetomidine, in the mouse hot plate and tail flick models of acute pain [83]; -CP55940 and the N-methyl-D-aspartate (NMDA) receptor antagonist, (-)-6-phosphonomethyl-decahydroisoquinoline-3-carboxylic acid (LY235959), in the mouse hot plate test [90]; and -R-(þ)-WIN55212, given by intracerebroventricular or intraplantar injection, and a selective agonist for the neuropeptide FF 1 or FF 2 receptor, injected intracerebroventricularly, in mouse models of acute pain [91].…”

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

“…For example, cannabinoid receptor agonists enhance the antinociceptive effects and hyperlocomotion induced by morphine in rodents (25). The discriminative stimulus effects of THC could be attenuated by μ-opioid receptor agonists (29). Further, cannabinoid receptor agonist abolished the rewarding effects of morphine (30).…”