Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain.
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.
Zhao
Peng
P
Department of Neurology and Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, NY 12208, USA Department of Neurology, UCSF Pain Clinical Research Center, University of California, San Francisco, CA 94115, USA Pain Relief Unit, Rambam Medical Center, Haifa, Israel Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Upstate Neurology Consultants, Albany, NY 12205, USA.
Barr
Travis P
TP
Hou
Quanzhi
Q
Dib-Hajj
Sulayman D
SD
Black
Joel A
JA
Albrecht
Phillip J
PJ
Petersen
Karin
K
Eisenberg
Elon
E
Wymer
James P
JP
Rice
Frank L
FL
Waxman
Stephen G
SG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D004817:Epidermis / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D009419:Nerve Tissue Proteins; D015222:Sodium Channels