Activation of 5-HT1A receptors in the ventrolateral orbital cortex alleviates neuropathic pain-induced depressive-like behaviors via GABAergic neurons in male rats.

Neuropathic pain is frequently comorbid with depression, which exacerbates patient suffering and complicates clinical management. Although the ventrolateral orbital cortex (VLO) is involved in pain processing and emotional regulation, its specific role in neuropathic pain-induced depression remains unclear. Emerging evidence implicates 5-HT1A receptors in modulating both pain and mood disorders via GABAergic transmission, yet their specific contributions in the VLO are not fully understood. Here, we aimed to investigate whether and how VLO 5-HT1A receptors mediate depressive-like behaviors associated with neuropathic pain in male rats. Using a spared nerve injury (SNI) model, combined with neuropharmacological, chemogenetic, and cell-type-specific adeno-associated virus (AAV) approaches, we found that activating VLO 5-HT1A receptor produced dose-dependent antidepressant effects, which were blocked by a selective antagonist. Mechanistically, 5-HT1A receptor-mediated antidepressant effects were enhanced by a GABAA receptor antagonist and suppressed by a GABAA receptor agonist. Chemogenetic activation of VLO GABAergic neurons abolished the antidepressant effects of 5-HT1A receptor stimulation. Furthermore, SNI-induced depressive-like behaviors correlated with reduced 5-HT1A receptor expression in the VLO. AAV-mediated 5-HT1A receptor overexpression specifically on GABAergic neurons alleviated depressive-like behaviors in SNI rats, while knockdown induced depressive-like phenotypes in wild-type rats. In conclusion, our findings demonstrate that 5-HT1A receptors in the VLO alleviate neuropathic pain-induced depressive-like behaviors through a GABAergic disinhibition mechanism. This study highlights 5-HT1A receptors in the VLO as promising therapeutic targets for mood disturbances associated with neuropathic pain, offering a cortical framework for comorbid pain-depression pathophysiology.