THE ROLE OF CIRCADIAN GENES IN THE THERAPEUTIC EFFECTS OF DULOXETINE AS A TREATMENT FOR NEUROPATHIC PAIN

The antidepressant duloxetine, a serotonin-norepinephrine reuptake inhibitor, is used clinically as a first-line treatment for neuropathic pain. Its therapeutic efficacy relies on a local anti-neuroinflammatory effect within the dorsal root ganglia (DRG). However, the molecular mechanisms underlying this effect remain poorly documented. Transcriptomic analyses conducted on the DRGs of neuropathic mice reveal that chronic duloxetine treatment significantly modulates the circadian system, specifically by decreasing Bmal1 expression and increasing the expression of Per1 and Per2. To determine the functional importance of these genes in duloxetine’s therapeutic effect, we utilized mice with single or double genetic knock-out of the Per1 and Per2 genes. Assessment of mechanical and thermal sensitivity thresholds revealed a total loss of duloxetine's therapeutic effect in these mice. Furthermore, through pharmacological manipulations, we demonstrated that decreasing Bmal1 expression mimics the analgesic effect of duloxetine, whereas increasing its expression abolishes the antidepressant's efficacy. In conclusion, our work demonstrates that circadian genes are crucial for duloxetine’s analgesic effects against symptoms of neuropathic pain. Future research will aim to link this circadian modulation with duloxetine’s established anti-neuroinflammatory mechanisms. Ultimately, our goal is to improve current strategies and develop more effective treatments for patients suffering from neuropathic pain.