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Emerging evidence suggest that the suppressive modulators released from nociceptive afferent neurons contribute to pain regulation.However, the suppressive modulators expressed in small-diameter neurons of the dorsal root ganglion (DRG) remain to be further identified.We find that the activin C expressed in small dorsal root ganglion neurons is required for suppressing inflammation-induced nociceptive responses.The expression of activin C in small DRG neurons of rats was markedly down-regulated during the early days of peripheral inflammation induced by intraplantar injection of the complete Freunds adjuvant (CFA).Intrathecal treatment with the small interfering RNA targeting activin βC or the antibodies against activin C could enhance the formalin-induced nociceptive responses, and impaired the recovery from the CFA-induced thermal hyperalgesia.Intrathecally applied activin C could reduce nociceptive responses induced by formalin or CFA.Moreover, activin C was found to inhibit the inflammation-induced phosphorelation of extracellular signal-regulated kinase in the dorsal root ganglia and the dorsal spinal cord.Thus,activin C functions as an endogenous suppressor of inflammatory nociceptive transmission and may have a therapeutic potential for treatment of inflammatory pain.