Fluoxetine reverses hyperactivity of anterior cingulate cortex and attenuates chronic stress-induced hyperalgesia.

Somatic symptom disorder (SSD), which occurs in about 5–7 percent of the adult population, involves heightened physical and emotional sensitivity to pain. However, its neural mechanism remains elusive and thus hinders effective clinical intervention. In this study, we employed chronic restraint stress (CRS)-induced hyperalgesia as a mouse model to investigate the neural mechanism underlying SSD and its pharmacological treatment. We found that CRS induced hyperactivity of anterior cingulate cortex (ACC), whereas chemogenetic inhibition of such hyperactivity could prevent CRS-induced hyperalgesia. Systematic application and ACC local infusion of fluoxetine alleviated CRS-induced hyperalgesia. Moreover, we found that fluoxetine exerted its anti-hyperalgesic effects through inhibiting the hyperactivity of ACC and upregulating 5-HT1A receptors. Our study thus uncovers the functional role of 5-HT signaling in modulating pain sensation and provides a neural basis for developing precise clinical intervention for SSD. • Chronic stress induces hyperactivity of ACC and hyperalgesia symptom in mouse model. • Fluoxetine lessens chronic stress-induced hyperalgesia and inhibits activity of ACC. • Fluoxetine reverses chronic stress induced-downregulation of 5-HT1A receptors in ACC. • Inhibition of 5-HT1A receptors abolishes anti-hyperalgesic effect of fluoxetine. [ABSTRACT FROM AUTHOR]