Heat But Not Mechanical Hypersensitivity Depends on Voltage-Gated Ca_V2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin

Abstract

Voltage-gated Ca_V2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. Ca_V2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor Ca_V2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional Ca_V2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that Ca_V2.2 channels in TRPV1-nociceptor endings are activated by capsaicin-induced depolarization and contribute to increased intracellular calcium. Capsaicin induces hypersensitivity of both thermal nociceptors and mechanoreceptors, but only heat hypersensitivity depends on peripheral Ca_V2.2 channel activity, and especially a cell-type-specific Ca_V2.2 splice isoform. Ca_V2.2 channels at peripheral nerve endings might be important therapeutic targets to mitigate certain forms of chronic pain.<b>SIGNIFICANCE STATEMENT</b> It is generally assumed that nociceptor termini in the spinal cord dorsal horn are the functionally significant sites of Ca_V2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral Ca_V2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of Ca_V2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related Ca_V2.1 channels. Our findings suggest that interrupting Ca_V2.2-dependent calcium entry in skin might reduce heat hypersensitivity that develops after noxious heat exposure and may limit the degree of heat hypersensitivity associated with certain other forms of pain.