Khodorova Alla, Navarro Betsy, Jouaville Laurence Sophie, Murphy Jo-Ellen, Rice Frank L, Mazurkiewicz Joseph E, Long-Woodward Denise, Stoffel Markus, Strichartz Gary R, Yukhananov Rus, Davar Gudarz
Molecular Neurobiology of Pain Laboratory, Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115 USA.
Nat Med. 2003 Aug;9(8):1055-61. doi: 10.1038/nm885. Epub 2003 Jun 29.
Endothelin-1 (ET-1) is a newly described pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A (ET(A)) receptors of local nociceptors, it can coincidentally produce analgesia through endothelin-B (ET(B)) receptors. Here we map a new endogenous analgesic circuit, in which ET(B) receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs, also named Kir-3) linked to opioid receptors on nociceptors. These results indicate the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and establish keratinocytes as an ET(B) receptor-operated opioid pool.
内皮素-1（ET-1）是一种新发现的疼痛介质，参与从创伤到癌症等各种疼痛状态的发病机制。ET-1由正常皮肤中的角质形成细胞合成，并在皮肤损伤后局部释放。虽然它能够通过作用于局部伤害感受器的内皮素-A（ET(A)）受体引发疼痛，但它也能通过内皮素-B（ET(B)）受体产生镇痛作用。在此，我们绘制了一条新的内源性镇痛回路，其中ET(B)受体激活诱导角质形成细胞释放β-内啡肽，并激活与伤害感受器上阿片受体相连的G蛋白偶联内向整流钾通道（GIRKs，也称为Kir-3）。这些结果表明存在一种内在反馈机制来控制皮肤中的外周疼痛，并将角质形成细胞确立为ET(B)受体介导的阿片类物质库。
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