Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.
Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.
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DOI：
10.1523/jneurosci.3229-12.2013
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发表时间：
2013-02-13
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影响因子：
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通讯作者：
Levine JD
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文献类型：
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作者：
Joseph EK;Green PG;Bogen O;Alvarez P;Levine JD
内皮素-1(ET-1)在一系列痛觉过敏药物中是独一无二的，因为它可以诱导大鼠的痛觉过敏，而在给药部位重复机械刺激会显著增强这种痛觉过敏。ET-1受体拮抗剂ETA和ETB可减弱内皮素性痛觉过敏(SIEH)的初始和刺激增强效应。然而，应用反义寡核苷酸抑制伤害性感受器上ETA受体的表达可减轻ET-1痛觉过敏，但对SIEH无影响，提示这是通过非神经细胞介导的。由于血管内皮细胞既是牵张敏感的，又表达ETA和ETB受体，我们验证了SIEH通过使用奥克索诺-9损害血管内皮细胞功能而依赖于内皮细胞的假说；该过程在不减弱ET-1痛觉过敏的情况下消除了SIEH。蛋白激酶C epsilon(PKCε)是第二信使，与慢性疼痛的诱导和维持有关。鞘内注射PKCε反义核酸不能抑制ET-1痛觉过敏或SIEH，提示神经元性PKCε不起作用；然而，在测试部位给予PKCε抑制剂选择性地减弱SIEH。P2X2/3受体拮抗剂可消除SIEH，这与机械刺激后内皮细胞释放ATP的作用相一致。在两种符合人体工程学的疼痛模型(偏心运动和后肢振动)和子宫内膜异位症模型中，内皮似乎也与痛觉过敏有关。我们认为SIEH的产生是由于ET-1对血管内皮细胞的作用，使其在机械刺激下敏化其释放的ATP；ATP反过来作用于伤害性感受器P2X2/3受体。
Endothelin-1 (ET-1) is unique amongst 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, ETA and ETB, attenuated both initial as well as stimulation-induced enhancement of hyperalgesia (SIEH) by endothelin. However, administering antisense oligodeoxynucleotide to attenuate ETA receptor expression on nociceptors attenuated ET-1 hyperalgesia, but had no effect on SIEH suggesting that this is mediated via a non-neuronal cell. Since vascular endothelial cells are both stretch-sensitive and express ETA and ETB 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 C epsilon (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, P2X2/3 receptor antagonists eliminated SIEH. The endothelium also appears to contribute to hyperalgesia in two ergonomic pain models (eccentric exercise and hind limb vibration) and in 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 P2X2/3 receptor.