Cytokine activin C ameliorates chronic neuropathic pain in peripheral nerve injury rodents by modulating the TRPV1 channel.

BACKGROUND AND PURPOSE Reportedly, cytokine activin C is mainly expressed in small-diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive. EXPERIMENTAL APPROACH Male rats, as well as wild type and transient receptor potential cation channel (TRP)V1 knockout mice, underwent peripheral nerve injury to establish chronic neuropathic pain. Ipsilateral lumbar (L)4~5 DRGs were assayed for activin C expression. Chronic neuropathic pain rat and mouse models were administered intrathecal or locally pre-administered activin C or the vehicle; then, nociceptive behaviors and pain-related markers in L4~5 DRGs and spinal cord were evaluated, and TRPV1 modulation by activin C was measured. KEY RESULTS Following peripheral nerve injury, the expression of activin βC subunit mRNA and activin C protein was markedly upregulated in L4~5 DRGs of experimental animals. Intrathecal activin C dose-dependently inhibited neuropathic pain in spinal nerve ligated rats. Local pre-administration of activin C decreased neuropathic pain, macrophage infiltration into ipsilateral L4~5 DRGs, and microglial reaction in L4~5 spinal cords of chronic constriction injury (CCI) mice. In rat DRG neurons, activin C enhanced capsaicin-induced TRPV1 currents. Pre-administration of activin C reduced capsaicin-evoked acute hyperalgesia and normalized capsaicin-evoked persistent hypothermia in mice. Finally, the analgesic effect of activin C was abolished in TRPV1 knockout mice following CCI. CONCLUSION AND IMPLICATIONS Activin C functions as an inhibitory regulator of neuropathic pain by modulating TRPV1 channels, revealing potential analgesic applications in chronic neuropathic pain therapy.