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...

Products containing naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073) are emerging drugs of abuse. Here, the behavioral effects of JWH-018 and JWH-073 were examined in one behavioral assay selective for cannabinoid agonism, rhesus monkeys (n ϭ 4) discriminating ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC; 0.1 mg/kg i.v.), and another assay sensitive to cannabinoid withdrawal, i.e., monkeys (n ϭ 3) discriminating the cannabinoid antagonist rimonabant (1 mg/kg i.v.) during chronic ⌬ 9 -THC (1 mg/kg s.c. 12 h) treatment. ⌬ 9 -THC, JWH-018, and JWH-073 increased drug-lever responding in monkeys discriminating ⌬ 9 -THC; the ED 50 values were 0.044, 0.013, and 0.058 mg/kg, respectively and the duration of action was 4, 2, and 1 h, respectively. Rimonabant (0.32-3.2 mg/kg) produced surmountable antagonism of ⌬ 9 -THC, JWH-018, and JWH-073. Schild analyses and single-dose apparent affinity estimates yielded apparent pA 2 /pK B values of 6.65, 6.68, and 6.79 in the presence of ⌬ 9 -THC, JWH-018, and JWH-073, respectively. In ⌬ 9 -THC-treated monkeys discriminating rimonabant, the training drug increased responding on the rimonabant lever; the ED 50 value of rimonabant was 0.20 mg/kg. ⌬ 9 -THC (1-10 mg/kg), JWH-018 (0.32-3.2 mg/kg), and JWH-073 (3.2-32 mg/kg) dose-dependently attenuated the rimonabantdiscriminative stimulus (i.e., withdrawal). These results suggest that ⌬ 9 -THC, JWH-018, and JWH-073 act through the same receptors to produce ⌬ 9 -THC-like subjective effects and attenuate ⌬ 9 -THC withdrawal. The relatively short duration of action of JWH-018 and JWH-073 might lead to more frequent use, which could strengthen habitual use by increasing the frequency of stimulusoutcome pairings. This coupled with the possible greater efficacy of JWH-018 at cannabinoid 1 receptors could be associated with greater dependence liability than ⌬ 9 -THC.

Supratherapeutic doses of the analgesic acetaminophen (paracetomol) are reported to promote social behavior in Swiss mice. However, we hypothesized that it might not promote sociability in other strains due to cannabinoid CB1 receptor-mediated inhibition of serotonin (5-HT) transmission in the frontal cortex. We examined the effects of acetaminophen on social and repetitive behaviors in comparison to a cannabinoid agonist, WIN 55,212-2, in two strains of socially-deficient mice, BTBR and 129S1/SvImJ (129S). Acetaminophen (100 mg/kg) enhanced social interactions in BTBR, and social novelty preference and marble burying in 129S at serum levels ≥70 ng/ml. Following acetaminophen injection or sociability testing, anandamide (AEA) increased in BTBR frontal cortex, while behavior testing increased 2-arachidonyl glycerol (2-AG) levels in 129S frontal cortex. In contrast, WIN 55,212-2 (0.1 mg/kg) did not enhance sociability. Further, we expected CB1-deficient (+/−) mice to be less social than wild-type, but instead found similar sociability. Given strain differences in endocannabinoid response to acetaminophen, we compared cortical CB1 and 5-HT1A receptor density and function relative to sociable C57BL/6 mice. CB1 receptor saturation binding (Bmax= 958±117 fmol/mg protein), and affinity for [3H]CP55,940 (KD= 3±0.8 nM) was similar in frontal cortex among strains. CP55,940-stimulated [35S]GTPγS binding in cingulate cortex was 136±12, 156±22, and 75±9% above basal in BTBR, 129S and C57BL/6 mice. The acetaminophen metabolite para-aminophenol (1μM) failed to stimulate [35S]GTPγS binding. Hence, it appears that other indirect actions of acetaminophen, including 5-HT receptor agonism, may underlie its sociability promoting properties outweighing any CB1 mediated suppression by locally-elevated endocannabinoids in these mice.

Cannabinoid CB 1 receptors are hypothesized to mediate the discriminative stimulus effects of cannabinoids. This study characterized a ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC; 0.1 mg/kg i.v.) discriminative stimulus and examined antagonism of cannabinoid agonists in rhesus monkeys. High levels of responding on the ⌬ 9 -THC lever were produced by cannabinoid agonists with the following rank order potency:, and noncannabinoids (cocaine, ketamine, midazolam, and morphine) did not produce high levels of ⌬ 9 -THC lever responding. The CB 1 -selective antagonist SR 141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] surmountably antagonized the discriminative stimulus effects of ⌬ 9 -THC and CP 55940, and Schild analysis was consistent with a simple, competitive interaction (apparent pA 2 values were 6.1 and 6.7, respectively). SR 141716A surmountably antagonized WIN 55212-2; however, larger doses disrupted responding, precluding Schild analysis. The CB 1 -selective antagonist AM 251 surmountably antagonized ⌬ 9 -THC, CP 55940, and WIN 55212-2, and Schild analysis was consistent with a simple, competitive interaction (apparent pA 2 values were 6.3, 6.1, and 6.2, respectively). The-THC discriminative stimulus. These results demonstrate that the discriminative stimulus effects of ⌬ 9 -THC are selective for cannabinoid activity, and the results of Schild analysis suggest that the same receptors mediate the discriminative stimulus effects of ⌬ 9 -THC, CP 55940, and WIN 55212-2. CB 2 receptors do not seem to mediate the discriminative stimulus effects of cannabinoid agonists. Schild analysis has the potential for identifying receptor subtypes that mediate the in vivo effects of cannabinoid agonists.

This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the ␣4␤2 receptor-selective antagonist dihydro-␤-erythroidine (DH␤E)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED 50 values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DH␤E, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DH␤E was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DH␤E-sensitive receptors (i.e., ␣4␤2) is unclear. The current nicotinediscrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has over behavior.