Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143-0440, USA.
J Neurosci. 2013 Feb 13;33(7):2849-59. doi: 10.1523/JNEUROSCI.3229-12.2013.
Endothelin-1 (ET-1) is unique among a broad range of hyperalgesic agents in that it induces hyperalgesia in rats that is markedly enhanced by repeated mechanical stimulation at the site of administration. Antagonists to the ET-1 receptors, ET(A) and ET(B), attenuated both initial as well as stimulation-induced enhancement of hyperalgesia (SIEH) by endothelin. However, administering antisense oligodeoxynucleotide to attenuate ET(A) receptor expression on nociceptors attenuated ET-1 hyperalgesia but had no effect on SIEH, suggesting that this is mediated via a non-neuronal cell. Because vascular endothelial cells are both stretch sensitive and express ET(A) and ET(B) receptors, we tested the hypothesis that SIEH is dependent on endothelial cells by impairing vascular endothelial function with octoxynol-9 administration; this procedure eliminated SIEH without attenuating ET-1 hyperalgesia. A role for protein kinase Cε (PKCε), a second messenger implicated in the induction and maintenance of chronic pain, was explored. Intrathecal antisense for PKCε did not inhibit either ET-1 hyperalgesia or SIEH, suggesting no role for neuronal PKCε; however, administration of a PKCε inhibitor at the site of testing selectively attenuated SIEH. Compatible with endothelial cells releasing ATP in response to mechanical stimulation, P2X(2/3) receptor antagonists eliminated SIEH. The endothelium also appears to contribute to hyperalgesia in two ergonomic pain models (eccentric exercise and hindlimb vibration) and in a model of endometriosis. We propose that SIEH is produced by an effect of ET-1 on vascular endothelial cells, sensitizing its release of ATP in response to mechanical stimulation; ATP in turn acts at the nociceptor P2X(2/3) receptor.
内皮素-1（ET-1）在广泛的痛觉过敏剂中是独特的，因为它在给予药物的部位反复机械刺激下诱导大鼠产生明显增强的痛觉过敏。ET-1 受体的拮抗剂，ET(A)和 ET(B)，减弱了 ET 诱导的痛觉过敏的初始和刺激诱导增强（SIEH）。然而，给予反义寡核苷酸以减弱伤害感受器上的 ET(A)受体表达减弱了 ET-1 痛觉过敏，但对 SIEH 没有影响，表明这是通过非神经元细胞介导的。由于血管内皮细胞既对拉伸敏感，又表达 ET(A)和 ET(B)受体，我们通过给予辛醇-9 来损伤血管内皮功能来测试 SIEH 是否依赖于内皮细胞的假说；这一过程消除了 SIEH，而不减弱 ET-1 痛觉过敏。还探讨了蛋白激酶 Cε（PKCε）的作用，PKCε 是一种涉及慢性疼痛的诱导和维持的第二信使。鞘内给予 PKCε 的反义寡核苷酸既不抑制 ET-1 痛觉过敏也不抑制 SIEH，表明神经元 PKCε 没有作用；然而，在测试部位给予 PKCε 抑制剂选择性地减弱了 SIEH。与内皮细胞在机械刺激下释放 ATP 相容，P2X(2/3)受体拮抗剂消除了 SIEH。内皮细胞似乎也参与了两种工效学疼痛模型（偏心运动和后肢振动）和子宫内膜异位症模型中的痛觉过敏。我们提出，SIEH 是由 ET-1 对血管内皮细胞的作用产生的，使其对机械刺激的释放敏感；ATP 反过来作用于伤害感受器 P2X(2/3)受体。
