BackgroundThe renin–angiotensin system (RAS) contributes to inflammatory and neuropathic pain, but whether its primary receptors, AT1R and AT2R, regulate the K2P channel TWIK1 in sensory neurons remains unknown. We investigated whether Ang-II receptors modulate TWIK1 expression and whether this pathway influences neuropathic pain.MethodsAdult female rats underwent chronic constriction injury (CCI) of the sciatic nerve and received continuous subcutaneous administration of vehicle, telmisartan (AT1R antagonist), PD123319 (AT2R antagonist), or their combination for 14 days. TWIK1, AT1R, and AT2R expression were analyzed in dorsal root ganglia (DRG) by immunohistochemistry and RT-qPCR. Behavioral outcomes included spontaneous foot lifting, cold allodynia, and mechanical hypersensitivity. Plasma cytokines were quantified by ELISA. Satellite glial cell (SGC) activation was assessed via GFAP immunoreactivity. In vitro DRG cultures were exposed to inflammatory stimuli to evaluate TWIK1 transcriptional regulation.ResultsCCI reduced TWIK1 expression in DRG neurons, accompanied by dynamic regulation of AT1R and AT2R. Pharmacological blockade, particularly combined receptor inhibition, restored or increased TWIK1 expression, attenuated mechanical and cold hypersensitivity, reduced circulating pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and decreased SGC activation. Inflammatory stimulation in vitro reduced TWIK1 mRNA, supporting cytokine-mediated regulation.ConclusionAT1R and AT2R regulate TWIK1 expression in sensory neurons through an integrated mechanism involving inflammatory signaling and glial activation. Dual receptor blockade produces the most consistent molecular and behavioral effects, supporting RAS modulation as a potential strategy for neuropathic pain management.