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Estrogen may affect pain perception while the underlying mechanisms remain unclear.In this investigation, pain behavior test, patch clamp recording, immunohistochemistry, western blotting and transgenic mice was undertaken to determine whether ATP receptor subunit, P2X3, is involved in the modulatory action of estrogen in peripheral pain signal transduction.17β-estradiol or estriol rapidly decreased αβ-meATP-induced spontaneous hind-paw withdrawal duration (PWD) in rats.PPT, G-1 but not DPN mimicked the effect.In small and medium-sized DRG neurons, ERα or GPR30 and P2X3 were coexpressed.17β-estradiol or estriol rapidly attenuated P2X3-induced transient currents, which was blocked by ICI 182,780, G-15, H-9, H-89, U0126 but not Go6976.The estrogen effect was absent in ERα(-/-) but present in ERβ(-/-) mice.Forskolin but not PMA mimicked the effect of estrogen.The effect of forskolin was blocked by U0126.17β-estradiol rapidly increased ERK1/2 phosphorylation in DRG neurons, which was blocked by G-15.Further, ovariectomy induced upregulation of P2X3 expression in DRG neurons which contributed to the mechanical hyperalgesia.The effect was reversed after 17β-estradiol replacement but not estriol.These results suggest that estrogen might participate in the control of peripheral pain signal transduction by inhibiting P2X3 receptor-mediated events via ERa and GPR30 in primary sensory neurons, probably through cAMP-PKA-ERK pathway.