Cannabinoid (CB) 1 receptor antagonists block fentanyl conditioned place preference but not fentanyl antinociception

Preclinical studies have found the cannabinoid (CB) 1 receptor inverse agonist/antagonist rimonabant and CB₁ neutral antagonists (AM4113, AM6527) to attenuate the addiction-related behavioral effects of opioids, suggesting that these drugs may be useful for managing opioid use disorder (OUD). However, the psychiatric side effect profile of rimonabant in clinical trials-an effect partially attributable to its inverse agonist activity-has impeded the clinical utility of CB₁ antagonists. Consequently, CB₁ neutral antagonists that are devoid of an inverse agonist-like side-effect profile may be useful as treatments for OUD. Here, we evaluated whether rimonabant, AM4113, and AM6527 attenuated the rewarding effects of fentanyl and whether they impacted its antinociceptive properties.

Conditioned place preference (CPP) procedures were used to analyze modulation of fentanyl-induced reward; CB₁ antagonists were administered either with fentanyl during conditioning (acquisition) or on test day after conditioning was complete (expression). Warm water tail withdrawal procedures were used to evaluate whether CB₁ antagonists modified the antinociceptive effects of fentanyl in mice.

Like rimonabant, the CB₁ neutral antagonists AM4113 and AM6527 attenuated both the acquisition and the expression of fentanyl-induced CPP. In the tail withdrawal experiments, the CB₁ antagonists did not alter fentanyl-induced antinociception and did not produce antinociceptive effects when administered on their own.

These results add to a growing body of evidence that CB₁ neutral antagonists can attenuate the rewarding properties of opioids while sparing their therapeutically desirable antinociceptive effects, providing support for further investigation of CB₁ neutral antagonists as possible treatments for OUD.