TRPA1 antagonism reveals sex-specific mechanisms in morphine withdrawal-induced negative emotional behavior via dopaminergic pathway.

Chronic opioid use facilitates changes in brain reward and affective systems. Cessation of opioid use induces negative affective states characterized by increased anxiety- and despair-like behaviors. In this study, the potential role of transient receptor potential ankyrin 1 channel (TRPA1) was assessed in morphine-induced dependence and negative emotional behaviors. Male and female C57BL/6J mice were exposed to escalating doses of morphine to induce dependence. Naloxone was administered to precipitate withdrawal symptoms. TRPA1 antagonism with A967079 treatment reduced withdrawal syndrome in both male and female mice. After 5 days of abstinence, mice were pre-treated with A967079 before behavioral tests to assess exploratory or anxiety-related, sociability, and despair-like behaviors induced by morphine withdrawal. We found a sex-specific effect of TRPA1 antagonism in different phases of addiction. For example, TRPA1 antagonism reduced withdrawal symptoms and immobility time during the tail suspension test. In contrast, only female mice showed improved sociability during the social interaction test. Additionally, enhanced immobility was observed in both sexes induced by A967079 treatment during the elevated plus maze. Additionally, involvement of the mesolimbic dopaminergic system was discovered to be sex- and brain region-specific in morphine withdrawal and abstinence, highlighting the importance of D2DR in modulating despair-like behavior via TRPA1 antagonism. Collectively, these results suggest that TRPA1 may modulate morphine dependence and negative affective states in a sex-dependent manner.