Anti-inflammatory and antinociceptive effects of fasudil in a reserpine-induced fibromyalgia model: Role of ROCK-regulated leptin-STAT3 signaling.

Fibromyalgia (FM) is a chronic widespread pain syndrome driven by macrophage-mediated neuroinflammatory changes within the dorsal root ganglia (DRG), which initiate maladaptive neuroimmune signaling that promotes peripheral nociception and central sensitization. Emerging evidence positions leptin and its downstream signaling networks as key regulators of nociceptive modulation and neuroinflammatory processes in chronic pain states. Leptin, a pleiotropic adipocytokine, exerts potent pro-nociceptive effects at the peripheral sensory ganglia through ObRb receptor engagement and downstream JAK2-STAT3 activation, amplifying macrophage-driven neuroinflammation within the DRG and sustaining peripheral sensitization, yet this axis remains a largely unexplored therapeutic target. To address this gap, the present study evaluated the ROCK inhibitor fasudil in a reserpine-induced FM model using adult male Wistar rats. Reserpine (1 mg/kg/day, s.c., 3 days) elicited FM-like phenotypes, followed by fasudil treatment (10 mg/kg, i.p., 14 days). Fasudil significantly suppressed ObRb-linked JAK2/STAT3 hyperactivation, modulating neurochemical dysregulation characterized by increased monoamines (serotonin, norepinephrine, dopamine) and GABA, alongside reduced excitatory mediators (glutamate, substance P), paralleling behavioral recovery from depressive-like states. Furthermore, fasudil exerted immunomodulatory effects by downregulating IL-1β, IL-6, iNOS, and CD86 in M1 macrophages, while enhancing Arg-1, IL-4, and CD163 expression to promote M2 polarization. This dual macrophage reprogramming attenuated neuroinflammation and fostered a neuroprotective milieu, preserving DRG integrity and significantly reducing pain behaviors (mechanical/thermal hyperalgesia and allodynia). Collectively, these findings identify fasudil as a promising therapeutic strategy for FM, acting through leptin-JAK2/STAT3 axis modulation to counteract neuroinflammation, restore neurotransmitter balance, and alleviate pain and affective symptoms.