Thalamic Purinergic Receptors: A Gateway to Modulating Fibromyalgia Pain via NLRP3 Inflammasome Signaling and Pyroptosis

Abstract The high pain sensitivity in fibromyalgia (FM) is processed by the thalamus that presents as a key component in the pain pathway in FM patients. Noteworthy, Purinergic receptors, specifically P2X, are implicated in pain signaling and neuroinflammation via inflammasome signaling. However, there is no available data on the impact of pharmacological intervention on P2X receptor in thalamic pain transmission in FM. To investigate this aspect, the clinically tested P2X inhibitor, Suramin (SURM), was utilized. FM was induced over three days using Reserpine (1 mg/kg/day, s.c.), followed by a single dose of SURM (100 mg/kg, i.p.). At the molecular level, SURM countered the overexpression of P2X7 and P2X4 receptors accompanied by reduced NLRP3 inflammasome complex and pyroptotic markers like gasdermin-D. This was associated by the suppression of the p38-MAPK and NF-κB pathways, along with a decrease in pro-inflammatory cytokines and tumor necrosis factor-α as observed by increased CD86 expression on M1 microglia phenotype, a neuroinflammatory marker. Concurrently, blocking the P2X receptor shifted microglia polarization towards the M2 phenotype, marked by elevated CD163 expression, as a neuroprotective mechanism. This was outlined by increased neurotrophic and anti-inflammatory; IL-10 with normalization of disturbed neurotransmitters. Behaviorally, SURM ameliorated the heightened pain processing, as observed in mechanical and thermal pain tests. Furthermore, it lowered Reserpine-induced motor impairment in the rotarod and open-field tests. This improvement in the somatosensory experience was reflected in alleviating depressive-like behavior in the forced swimming test. These findings highlight the therapeutic potential of blocking thalamic P2X receptors in alleviating fibromyalgia symptoms.