Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: Evidence for a role in pain

Abstract

Keratinocytes are implicated in sensory transduction and can influence nociception, but whether these contribute to chronic pain is not known. In neurons, voltage-gated sodium channels (Na(v)) are involved in neuropathic pain and are activated by depolarization. Since keratinocytes can also show changes in membrane potential, we used RT-PCR, in situ hybridization, and immunohistochemistry to investigate the expression of sodium channels in these cells. Na(v)1.1, Na(v)1.6, and Na(v)1.8 were localized within keratinocytes in rat epidermis. In addition, sodium channels contribute to the release of ATP from rat keratinocytes in response to increased [K(+)](o), implicating sodium channels in keratinocyte ligand release and nociception. To examine whether keratinocytes may contribute to human pain states, we analyzed sodium channel expression in human skin biopsies from subjects with complex regional pain syndrome Type 1 (CRPS) and post-herpetic neuralgia (PHN) using immunohistochemistry. Control skin exhibited immunolabeling for Na(v)1.5, Na(v)1.6 and Na(v)1.7. In contrast, painful skin from CRPS and PHN subjects displayed Na(v)1.1, Na(v)1.2, and Na(v)1.8 immunolabeling, in addition to substantially increased signal for Na(v)1.5, Na(v)1.6, Na(v)1.7. These observations lead us to propose that pathological increases in keratinocyte sodium channel expression may contribute to pain by increasing epidermal ATP release, resulting in excessive activation of P2X receptors on primary sensory axons. Consistent with this hypothesis, animal models of neuropathic pain exhibit increases in subcutaneous ATP release and activity of primary sensory neurons, and peripheral administration of P2X antagonists has been shown to reduce neuropathic pain in humans.

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

“…The only drugs known to interact with Nav1.2 are the anticonvulsants. Nav1.2 is expressed on keratinocytes and appears to be associated with pain [49]. Carbamazepine and phenytoin bind the same site on Nav1.2.…”

Inflammation in CRPS: Role of the sympathetic supply

“…This might be important in CRPS. For instance, Zhao et al (Zhao et al, 2008) reported that sodium channel expression was increased in the keratinocyte layer of patients with CRPS and post herpetic neuralgia, and the beta-isoform of the inflammatory neuropeptide CGRP was found to be increased in keratinocytes both in CRPS patients and in animal models of pain (Hou et al, 2011).…”

Topical Phenytoin in Neuralgic Pain, Peripheral Modulation of Central Sensitization: Two Case Reports

“…Sadly enough only fragmentary insight exists in the role and the peripheral expression of sodium channels in pain-transducing free nerve ending in the skin and on the keratinocytes [28]. The sodium channels, Nav1.1, Nav1.6 and Nav1.8 are abundantly present at epidermal keratinocytes [29]. These sodium channel have differential patterns of distribution within the epidermis.…”

“…Labeled axons within the dermis were detected for Nav1.2, Nav1.7, Nav1.8 and Nav1.9, but its immunolabeling was much less intense compared to the keratinocytes. It was suggested that these channels could possibly contribute to pain [29]. Pathological increases have been documented in keratinocyte sodium channel expression found in skin biopsies of patients suffering from neuropathic pain [29].…”