Heat But Not Mechanical Hypersensitivity Depends on Voltage-Gated Ca(V)2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin

Voltage-gated Ca(V)2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. Ca(V)2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor Ca(V)2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional Ca(V)2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that Ca(V)2.2 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(V)2.2 channel activity, and especially a cell-type-specific Ca(V)2.2 splice isoform. Ca(V)2.2 channels at peripheral nerve endings might be important therapeutic targets to mitigate certain forms of chronic pain. SIGNIFICANCE STATEMENT It is generally assumed that nociceptor termini in the spinal cord dorsal horn are the functionally significant sites of Ca(V)2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral Ca(V)2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of Ca(V)2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related Ca(V)2.1 channels. Our findings suggest that interrupting Ca(V)2.2-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.