Melatonin Mitigates Central Sensitization and Nociplastic Pain in Spinal Cord and Dorsal Root Ganglia of FM Rat Model: Modulation of SIRT1/PGC-1α/MAPK/NF-κB Signaling.

Fibromyalgia (FM) is a central sensitization syndrome characterized by neuroinflammation and synaptic hyperexcitability, which amplifies pain signals in the spinal cord (SC) and dorsal root ganglia (DRG). Melatonin (MEL) has demonstrated analgesic and antinociceptive properties in experimental models, supporting its clinical application in various pathological conditions. This study aimed to elucidate the impact of Melatonin on neuroinflammation and glutamatergic dysregulation in the spinal cord and DRG using a Reserpine-induced fibromyalgia model (RIFM). RIFM was induced in female rats by administering Reserpine (1 mg/kg/day, s.c.) for three consecutive days. Melatonin (10 mg/kg, orally) was administered for three days following the peak of pain on day 7. Melatonin significantly ameliorated stimulus-evoked pain in thermal and mechanical tests, with a resolution of spontaneous pain noted by the rat grimace scale. Moreover, motor activity in the open field task and depressive behavior in the tail suspension test (TST) were alleviated following Melatonin administration. Fibromyalgia pain was associated with enhanced glutamatergic transmission, as shown by immunohistochemical assessment of synaptophysin and PSD95 in the DRG along with VGLUT, PSD95, NMDA, NMDA receptor 2B, and AMPA in the spinal cord. Reserpine-induced disturbances in mitochondrial biogenesis markers, SIRT1 and PGC-1α, were followed by an upsurge of TNF-α, NFkB, and P38-MAPK. This neuroinflammatory milieu was marked by elevated ionized calcium-binding adaptor molecule-1 (Iba-1) in activated microglia within the spinal cord. These pathological findings were notably mitigated by Melatonin, as reflected by increased expressions of spinal MT1 and MT2 receptors. In conclusion, Melatonin exhibited antinociceptive and anti-inflammatory effects by modulating glutamate neurotransmission, mitochondrial dysfunction, and microglial activation, thereby alleviating nociplastic pain in the experimental RIFM. GRAPHICAL ABSTRACT: The potential role of Melatonin in modulating Reserpine-induced fibromyalgia in rats through MT1R and MT2R receptors [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11481-025-10274-7.