Abstract
We previously showed that Kv3.4 channels underlie most of the high-voltage activated K+ current (IKHV) in dorsal root ganglion (DRG) nociceptors and elimination of Kv3.4 N-type inactivation by protein kinase C-dependent phosphorylation enhances the channel's ability to repolarize action potentials (APs) (Ritter et al. 2012 J Physiol 590:145-61). This function is important as reduction of Kv3.4 channel expression is found in diverse models of neuropathic pain. We hypothesize that phosphorylated Kv3.4 channels underlie an anti-nociceptive homeostatic mechanism in nociceptors that reduces downstream Ca++ signaling and down-regulation of Kv3.4 channel expression destroys this putative homeostatic mechanism, contributing to chronic pain. To test this hypothesis, we investigated a spinal cord injury (SCI) rat model of neuropathic pain in which a C5 hemi-contusion induces bilateral forepaw thermal hyperalgesia and mechanical allodynia 2 weeks post injury. In the contralateral SCI DRG, the peak IKHV is reduced by 55% and the time constant of inactivation (Taui) increases by 2-fold relative to laminectomy controls. Furthermore, while 85% of laminectomy nocicpetors show a fast inactivating Kv3.4 current, the SCI phenotypes fall into three categories: no current (25%), substantial sustained current (46%) or slow inactivation (29%, Taui >2 S.D. of controls). This suggests that Kv3.4 channels are phosphorylated and down-regulated in SCI. Confirming the impact of these changes on AP firing, AP-clamp experiments in SCI nociceptors show altered currents compared to controls. Interestingly, Kv3.4 mRNA splicing is altered in SCI DRG, which might alter the Kv3.4 channels' response to injury. We propose that Kv3.4 channels, their modulation by PKC and regulation of splicing are therapeutic targets in neuropathic pain.Supported by the Farber Family Foundation (MC), Sigma Xi GIAR (DR), Craig Nielson Foundation (AL), and Paralyzed Veterans of America (AL).
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