Background and purpouse Psychological disorders, such as anxiety and anhedonia are pain comorbidities, however how pain affects male and female individuals and through which mechanism is not well understood. Previous research show pain-induced alterations in the dynorphinergic pathway in the mesocorticolimbic system (MCLS) together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor involvement in these pain related behaviours. Experimental approach We used behavioural pharmacology and biochemical tools to characterize negative affective states induced by inflammatory pain in male and female rats, and the alterations in dynorphinergic and corticotropin systems in the MCLS. Key results. Female rats showed a persistent anxiety-like together with a reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations of in both dynorphin and corticotropin releasing factor in NAc and amygdala that suggest sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats. Conclusions and implications Our results show sex and time dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data pointing to the KOR/dyn recruitment in the NAc as key neurological substrate mediating these behaviours. This research encourages the study the mechanisms underlying these behaviours, to better understand the emotional dimension of pain.

Background and Purpose Pain-induced negative affect reduces life quality of patients by increasing psychiatric comorbidities, including alcohol use disorders (AUD). Indeed, clinical data suggest pain as a risk factor to suffer AUD, predicting relapse drinking in abstinent patients. Here, we analyse the impact of pain on alcohol relapse and the role of kappa opioid receptors (KOR) activation in mediating this pain-induced effects since KOR play an important role in pain-driven negative affect and AUD. Experimental approach Female and male Sprague Dawley rats underwent to two alcohol intermittent access periods separated by a forced abstinence period. The complete Freund adjuvant (CFA) model of inflammatory pain was introduced during abstinence and alcohol intake after alcohol reintroduction was assessed. Additionally, we used behavioural approaches to measure stress and memory impairment and biochemical assays to measure KOR expression in abstinence and reintroduction periods. Finally, KOR antagonist norbinaltorphimine (norBNI) was administered in the nucleus accumbens shell (NAcS) during abstinence to prevent pain-induced alcohol relapse-like phenomenon in CFA-female rats. Key results Only female CFA-treated rats increased alcohol intake during reintroduction period. Concomitantly, this group showed enhanced stress-like behaviour and increased KOR expression in the NAcS that was developed during abstinence and remained during reintroduction period. Finally, norBNI administered in the NAcS prevented pain-induced alcohol relapse-like behaviour in female rats. Conclusions and implications Our data evidenced that inflammatory pain constitutes a risk factor to relapse only in female rats, by the arise and maintenance of stress probably mediated by kappa opioid receptor (KOR) signaling in the NAcS.