Stress- induced changes in endocannabinoid system: gender differences and interaction with opioid receptors

Chronic stress induces persistent maladaptive changes in the nucleus accumbens (NAc) that increase vulnerability to substance use disorders. The endogenous opioid (EOS) and endocannabinoid (eCB) systems converge in the NAc to regulate stress responses and neurotransmission. Our previous work showed that CB1R signaling participates in stress-induced reinstatement of cocaine-seeking behavior. Likewise, alterations in the EOS have been implicated in stress- and drug-induced adaptations. However, the effects of chronic stress on the eCB system in the NAc and the contribution of opioid receptor signaling to these changes in a sex-dependent manner remain poorly understood. Thus, we investigated this interaction using naloxone. Male and female mice underwent chronic stress (6 days, 2 h/day), followed by naloxone (1 mg/kg/day, i.p.) for 5 days. On day 21, NAc levels of μ-opioid receptor, proenkephalin (Penk), CB1R, and eCB machinery components were evaluated. Chronic stress increased Penk and CB1R levels in both sexes, with naloxone preventing the stress-induced increase in CB1R but not Penk upregulation. Stress also altered eCB machinery in a sex-dependent manner. These findings suggest that opioid receptor signaling contributes to stress-induced remodeling of the eCB system in the NAc core, supporting functional opioid–endocannabinoid interactions and highlighting opioid signaling as a potential target for stress-related neuropsychiatric conditions.