Involvement of the cannabinoid system in stress-induced reinstatement to opioid use: a study in CB1 knockout mice of both sexes.

Deaths related to opioid use have increased in men and women of all ages and socioeconomic status. The Cannabinoid receptor 1 (CB1R) has been reported to be involved in the coordination of behaviours related to reward-related associative learning, motivational behaviours related to drug abuse and the conditioned rewarding effect of opioids. However, little is known about the involvement of CB1R in the reinstatement of stress-induced morphine rewarding effect. The present work represents the first study aimed at studying the effect of physical stress and the involvement of the CB1R in the phenomenon of opiate-induced conditioned place preference (CPP) extinction and reinstatement in CB1 knockout (CB1 KO) mice and their respective Wild-Type (WT) of both sexes. The rewarding effects of morphine (10 mg/kg, sc) was confirmed by using the (CPP) followed by an extinction phase with 10 saline sessions (0.10 ml/g, sc) and a stress-tested reinstatement due to immobilisation. Morphine induced significant CPP in both WT and CB1 KO mice of both sexes, with an enhanced rewarding effect observed in CB1 KO mice. CPP extinction occurred only in WT animals of both sexes; however. Stress-induced reinstatement of CPP was observed exclusively in WT females, but was absent in CB1 KO mice of both sexes. In conclusion, our results provide novel and significant evidence for the involvement of the cannabinoid system in the conditioning-extinction-reinstatement of the rewarding effect of morphine, showing a differential involvement in the stages analysed in this study.