TRPV3 modulates nociceptive signaling through peripheral and supraspinal sites in rats.

Abstract

TRPV3 is a nonselective cation channel activated by temperatures above 33°C and is reported to be localized in keratinocytes and nervous tissue. To investigate a role for TRPV3 in pain modulation, we conducted a series of in vivo electrophysiological studies on spinal and brain nociceptive neurons. Structurally diverse TRPV3 receptor antagonists reduced responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in neuropathic rats, but only CNS-penetrant antagonists decreased elevated spontaneous firing. Injections of an antagonist into the neuronal receptive field, into the L5 dorsal root ganglion, or intracerebroventricularly (ICV) attenuated the evoked firing, but only ICV injections reduced spontaneous activity. Intraspinal injections did not affect either. Spinal transection blocked the effect on spontaneous but not evoked firing after systemic delivery of a TRPV3 antagonist. Systemic administration of an antagonist to neuropathic rats also impacted the firing of On- and Off-cells in the rostral ventromedial medulla in a manner consistent with dampening nociceptive signaling. An assessment of nonevoked "pain," an EEG-measured pain-induced sleep disturbance induced by hind paw injections of CFA, was also improved with CNS-penetrant TRPV3 antagonists but not by an antagonist with poor CNS penetration. Antagonism of TRPV3 receptors modulates activity of key classes of neurons in the pain pathway in a manner consistent with limiting pathological nociceptive signaling and was mediated by receptors in the periphery and brain. Blockade of TRPV3 receptors is likely an effective means to alleviate mechanical allodynia and nonevoked pain. However, the latter will only be obtained by blocking supraspinal TRPV3 receptors.NEW & NOTEWORTHY Recent studies have linked TRPV3 to pain modulation, and much of this work has focused on its role in the skin-primary afferent interface. In this electrophysiological study, we demonstrate that receptor antagonists modulate evoked signals through peripheral mechanisms but blockade of supraspinal TRPV3 receptors contributes to dampening both evoked and nonevoked "pain" through descending modulation. Thus, the full therapeutic potential of TRPV3 antagonists may only be realized with the ability to access receptors in the brain.