Heat But Not Mechanical Hypersensitivity Depends on Voltage-Gated Ca<sub>V</sub>2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin
D Dubreuil, Eduardo Javier López Soto, Simon Daste, R. Meir, Dan Li, Brian J. Wainger, Alexander Fleischmann, Diane Lipscombe
Abstract
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.