Abstract
Voltage-gated CaV2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional CaV2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that CaV2.2 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 CaV2.2 channel activity, and especially a cell-type-specific CaV2.2 splice isoform. CaV2.2 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 CaV2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral CaV2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of CaV2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related CaV2.1 channels. Our findings suggest that interrupting CaV2.2-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.
Highlights
Voltage-gated calcium channels CaV2.2 (N-type current) and CaV2.1 (P-type current) are the primary sources of calcium that control neurotransmitter release from nociceptor presynaptic termini in the spinal cord dorsal horn (Diaz and Dickenson, 1997; Heinke et al, 2004; Motin and Adams, 2008; Jayamanne et al, 2013)
CaV2.2 channels contribute to heat and mechanical sensitivity CaV2.1 and CaV2.2 channels support transmitter release from presynaptic sensory terin whole brain lysate from WT mice and its absence in CaV2.2-null mice (KO)
Our data show that CaV2.2 channel activity in transient receptor potential vanilloid 1 (TRPV1) nociceptor nerve endings in skin is critical for capsaicin-induced transient hyperalgesia to heat but not for mechanical hypersensitivity (Figs. 4, 5)
Summary
Voltage-gated calcium channels CaV2.2 (N-type current) and CaV2.1 (P-type current) are the primary sources of calcium that control neurotransmitter release from nociceptor presynaptic termini in the spinal cord dorsal horn (Diaz and Dickenson, 1997; Heinke et al, 2004; Motin and Adams, 2008; Jayamanne et al, 2013). Opioids act through m-opioid receptors and inhibit the gating of presynaptic Cav2.2 channels in the spinal cord dorsal horn and decrease synaptic transmission (Horváth et al, 2001; Andrade et al, 2010). DuBreuil, Lopez Soto et al · Peripheral CaV2.2 Channels Control Heat Hypersensitivity. CaV2.2-e37a channels appear to be critical for some forms of hyperalgesia, CaV2.2 splice isoforms contribute to acute nociception (Altier et al, 2007; Andrade et al, 2010)
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