Zhao Peng, Barr Travis P, Hou Quanzhi, Dib-Hajj Sulayman D, Black Joel A, Albrecht Phillip J, Petersen Karin, Eisenberg Elon, Wymer James P, Rice Frank L, Waxman Stephen G
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.
Pain. 2008 Sep 30;139(1):90-105. doi: 10.1016/j.pain.2008.03.016. Epub 2008 Apr 28.
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(+), 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.
角质形成细胞参与感觉传导并能影响伤害感受，但这些是否会导致慢性疼痛尚不清楚。在神经元中，电压门控钠通道（Na(v)）参与神经性疼痛并通过去极化激活。由于角质形成细胞也能表现出膜电位变化，我们使用逆转录聚合酶链反应（RT-PCR）、原位杂交和免疫组织化学来研究这些细胞中钠通道的表达。Na(v)1.1、Na(v)1.6和Na(v)1.8定位于大鼠表皮的角质形成细胞内。此外，钠通道有助于大鼠角质形成细胞在细胞外钾离子浓度（K(+)）升高时释放三磷酸腺苷（ATP）,这表明钠通道参与角质形成细胞配体释放和伤害感受。为了研究角质形成细胞是否可能导致人类疼痛状态，我们使用免疫组织化学分析了来自1型复杂性区域疼痛综合征（CRPS）和带状疱疹后神经痛（PHN）患者的人体皮肤活检样本中钠通道的表达。对照皮肤显示出Na(v)1.5、Na(v)1.6和Na(v)1.7的免疫标记。相比之下，CRPS和PHN患者的疼痛皮肤除了Na(v)1.5、Na(v)1.6、Na(v)1.7信号大幅增加外，还显示出Na(v)1.1、Na(v)1.2和Na(v)1.8的免疫标记。这些观察结果使我们提出，角质形成细胞钠通道表达的病理性增加可能通过增加表皮ATP释放导致疼痛，从而导致初级感觉轴突上P2X受体的过度激活。与这一假设一致，神经性疼痛的动物模型表现出皮下ATP释放增加和初级感觉神经元的活性增加，并且已证明外周给予P2X拮抗剂可减轻人类的神经性疼痛。
