Effects of Cannabinoid Receptor Agonists on the Antinociceptive Effects of Oxycodone in Squirrel Monkeys

Opioids remain the most commonly prescribed drug class for the management of moderate to severe pain and, often, high doses that have unwanted behavioral effects are required for effective analgesia. One strategy that has been proposed to avoid prescribing high doses of opioids is co‐administration of a cannabinoid such as Δ 9 ‐tetrahydrocannabinol (THC) that, by providing its own analgesic effects, will reduce opioid dosage. Studies using the warm water tail withdrawal assay, which remains the most commonly used method for assessing antinociception across species, have provided encouraging data in support of this approach. Here, we further study the potential clinical advantage of this approach by determining how different cannabinoid agonists modify the effects of oxycodone on tail withdrawal latency and food‐maintained behavior (reinforcement density, response rate) in squirrel monkeys. Daily sessions were comprised of four 5‐min response components, each preceded by a long timeout during which cumulative doses of drugs (10‐min for oxycodone and 30‐min for THC or the nabilone derivative AM 7444) could be administered. During each component, the completion of a 10‐response fixed‐ratio in the presence of stimulus lights initiated food delivery and a 30‐sec short timeout during which stimulus lights were off and tail withdrawal latency was measured. Results show that all three drugs produced dose related decreases on both measures of food‐maintained behavior but only oxycodone (0.032–0.56 mg/kg) and AM 7444 (0.0032–0.032 mg/kg) produced dose dependent increases in tail withdrawal latency. These antinociceptive effects were produced by doses of both drugs that did not greatly reduce reinforcement density and were more pronounced for oxycodone than the cannabinoid. Pretreatment with the highest dose of THC that did not eliminate responding (0.32 mg/kg) shifted the dose‐effect function for oxycodone's antinociceptive effects upward and leftward and its effects on food‐maintained behavior downward and leftward. Pretreatment with 0.0032 or 0.0056 mg/kg of AM7444 did not appreciably alter the antinociceptive effects of oxycodone whereas pretreatment with the higher dose (0.0056 mg/kg) markedly accentuated the effects of oxycodone on food‐maintained behavior. These data support previous findings that cannabinoid pretreatment can heighten the antinociceptive effects of morphine‐like opioids but indicate also that cannabinoid pretreatment may exacerbate their behaviorally disruptive effects. Thus, this approach to pain management, while effective, may not be appropriate for all therapeutic settings.