Involvement of JAK2/STAT3, PI3K/AKT/mTOR, and M1/M2 microglial polarization in the possible effects of baricitinib for mitigating reserpine-induced fibromyalgia in rats.

Abstract

Fibromyalgia (FM) is a chronic pain disorder characterized by widespread musculoskeletal pain accompanied by fatigue, mood disturbances, and sleep abnormalities. Baricitinib, a selective Janus kinase (JAK) 1/2 inhibitor, has potent anti-inflammatory and immunomodulatory effects and is approved for various resistant inflammatory conditions. The present study aimed to investigate the therapeutic potential of baricitinib against fibromyalgia-like manifestations induced by reserpine in rats. Reserpine (1 mg/kg/day, subcutaneous) was administered for three consecutive days to induce FM-like pathology, followed by oral treatment with baricitinib at low and high doses for 14 consecutive days. Reserpine administration resulted in marked neuroinflammatory changes, evidenced by elevated levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α, along with increased phosphorylation of JAK2, STAT3, PI3K, AKT, and mTOR signaling proteins. Baricitinib treatment significantly ameliorated these molecular alterations and attenuated histopathological damage in the spinal cord. Furthermore, baricitinib partially restored dopamine D2 receptor levels and modulated M1/M2-associated microglial markers, as indicated by reduced CD86 expression and enhanced CD163 immunoreactivity. Additionally, behavioral assessments demonstrated significant improvements in pain sensitivity, locomotor activity, and depressive-like symptoms. These findings highlight the neuroprotective and anti-inflammatory effects of baricitinib in a reserpine-induced fibromyalgia model and support its potential role in targeting neuroimmune mechanisms underlying fibromyalgia.