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 Δ 9 -tetrahydrocannabinol (Δ 9 -THC) have been reported to potentiate oxycodone-induced antinociception in animals and humans. Whether Δ 9 -THC also facilitates unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at antinociceptive doses, remains unclear. We evaluated co-administration of Δ 9 -THC and oxycodone on antinociception, dependence, circadian activity, and reward in male and female mice. Oxycodone and Δ 9 -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. Δ 9 -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 co-treatment with Δ 9 -THC. Combination treatment of oxycodone and Δ 9 -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 Δ 9 -THC potentiated oxycodone-evoked dopamine release at sub-effective oxycodone doses, a candidate mechanism for the behavioral reward potentiation. These data indicate that Δ 9 -THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (e.g., dependence, circadian rhythm alterations). However, Δ 9 -THC also recruited the rewarding properties of oxycodone at therapeutically relevant doses. These reward-related findings indicate that Δ 9 -THC and oxycodone combinations may carry increased abuse liability, a primary consideration for their therapeutic evaluation.