Impact of Δ9-tetrahydrocannabinol and oxycodone coadministration on measures of antinociception, dependence, circadian activity, and reward in mice.

Oxycodone is commonly prescribed for moderate-to-severe pain. While efficacious, long-term use can result in tolerance, physical dependence, and opioid use disorder. Cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) have been reported to potentiate oxycodone-induced antinociception in animals and humans. Whether Δ9-THC also facilitates unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at antinociceptive doses, remains unclear. We evaluated the coadministration of Δ9-THC and oxycodone on antinociception, dependence, circadian activity, and reward in male and female mice. Oxycodone and Δ9-THC produced dose-dependent antinociception in the hotplate assay, with oxycodone showing lower potency in females. Repeated treatment (twice daily for 5 days) produced antinociceptive tolerance. Δ9-THC produced a potentiation-like effect on oxycodone-induced antinociception and delayed antinociceptive tolerance. Repeated oxycodone produced physical dependence and alterations in circadian activity, neither of which was exacerbated by cotreatment with Δ9-THC. Combination treatment of oxycodone and Δ9-THC produced conditioned place preference at doses that did not produce preference when administered alone. Fiber photometry recordings of nucleus accumbens dopamine release showed that Δ9-THC potentiated oxycodone-evoked dopamine release at subeffective oxycodone doses, a candidate mechanism for the behavioral reward potentiation. These data indicate that Δ9-THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (eg, dependence and circadian rhythm alterations). However, Δ9-THC also recruited the rewarding properties of oxycodone at therapeutically relevant doses. These reward-related findings indicate that Δ9-THC and oxycodone combinations may carry increased abuse liability, a primary consideration for their therapeutic evaluation. SIGNIFICANCE STATEMENT: In mice, Δ9-tetrahydrocannabinol (Δ9-THC) produced a potentiation-like effect on oxycodone-induced antinociception and delayed antinociceptive tolerance without exacerbating opioid dependence or circadian disruption, but Δ9-THC also produced conditioned place preference and potentiated nucleus accumbens dopamine release at subeffective oxycodone doses. These findings indicate that Δ9-THC may enhance oxycodone-induced antinociception, but also that Δ9-THC recruits the rewarding properties of oxycodone at doses that are otherwise subeffective. The increased abuse liability of such combinations is a primary consideration for their therapeutic evaluation.