CONICET | Buscador de Institutos y Recursos Humanos

Ongoing/spontaneous pain behaviour is associated with ongoing/spontaneous firing (SF) in adult dorsal root ganglion (DRG) C-fiber nociceptors (Djouhri et al., 2006). Causes of this SF are not understood. We show here that conducting (sometimes called uninjured) C-nociceptors in neuropathic pain models with more hyperpolarised resting membrane potentials (Ems) have lower SF rates. Understanding the control of their Ems may therefore be important for limiting pathological pain. We report that TREK2, a leak K+ channel, is selectively expressed in IB4-binding rat C-nociceptors. These IB4+ve C-neurons are ~10mV more hyperpolarised than IB4-ve C-neurons in vivo (Fang et al., 2006). TREK2-knockdown by siRNA in these neurons in culture depolarised them by ~10mV, suggesting that TREK2 is responsible for this ~10mV difference. In vivo, more hyperpolarised C-nociceptor Ems were associated with higher cytoplasmic edge-TREK2 expression (edge-TREK2). Edge-TREK2 decreased in C-neurons 7d after axotomy, and their Ems depolarised by ~10mV. This again supports a contribution of TREK2 to their Ems. These relationships between a) Em and TREK2, b) SF rate and Em, and c) spontaneous pain behaviour and C-nociceptor SF rate suggested that TREK2 knockdown might increase spontaneous pain. After CFA-induced inflammation, spontaneous foot lifting (a measure of spontaneous pain) was a) greater in rats with naturally lower TREK2 in ipsilateral small DRG neurons and b) was increased by siRNA-induced TREK2-knockdown in vivo. We conclude that TREK2 hyperpolarises IB4-binding C-nociceptors and limits pathological spontaneous pain. Similar TREK2 distributions in small DRG neurons of several species suggest that these role/s of TREK2 may be widespread.