Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell

Abstract

Background and purpose: 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.