Integrin signaling in inflammatory and neuropathic pain in the rat
Integrin signaling in inflammatory and neuropathic pain in the rat
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DOI：
10.1111/j.1460-9568.2004.03169.x
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发表时间：
2004-02-01
影响因子：
3.4
通讯作者：
Levine, JD
中科院分区：
文献类型：
--
作者：
Dina, OA;Parada, CA;Levine, JD
许多疼痛状况与受影响组织的细胞外基质（ECM）的改变有关。虽然几种整合素，ECM蛋白的受体，存在于介导疼痛的感觉神经元上，但这些细胞粘附分子在炎症性或神经性疼痛中的可能作用尚未被探索。我们发现，皮内注射层粘连蛋白和纤连蛋白对粘附信号传导有重要作用的结构域的肽段分别选择性地抑制前列腺素E-2（PGE（2））和肾上腺素（EPI）引起的痛觉过敏。针对参与层粘连蛋白结合的α（1）或α（3）整联蛋白亚基的单克隆抗体（mAb）选择性阻断PGE（2）痛觉过敏，而针对参与纤连蛋白结合的α（5）亚基的mAb仅阻断EPI诱导的痛觉过敏。针对层粘连蛋白和纤连蛋白受体共同的β（1）整合素亚基的单克隆抗体抑制了由两种药物引起的痛觉过敏，鞘内注射反义寡脱氧核苷酸敲低β（1）整合素表达也是如此。层粘连蛋白肽，但不是纤连蛋白肽，也可逆地消除了较长时间的炎性痛觉过敏角叉菜胶诱导。最后，由全身给予癌症化疗剂紫杉醇引起的神经性痛觉过敏被β（1）整合素的反义敲低可逆地抑制。这些结果强烈暗示特定的整合素在维持炎症性和神经性痛觉过敏。
Many painful conditions are associated with alterations in the extracellular matrix (ECM) of affected tissues. While several integrins, the receptors for ECM proteins, are present on sensory neurons that mediate pain, the possible role of these cell adhesion molecules in inflammatory or neuropathic pain has not been explored. We found that the intradermal injection of peptide fragments of domains of laminin and fibronectin important for adhesive signaling selectively inhibited the hyperalgesia caused by prostaglandin E-2 (PGE(2)) and epinephrine (EPI), respectively The block of EPI hyperalgesia was mimicked by other peptides containing the RGD integrin-binding sequence. Monoclonal antibodies (mAbs) against the alpha(1) or alpha(3) integrin subunits, which participate in laminin binding, selectively blocked PGE(2) hyperalgesia, while a mAb against the alpha(5) subunit, which participates in fibronectin binding, blocked only EPI-induced hyperalgesia. A mAb against the beta(1) integrin subunit, common to receptors for both laminin and fibronectin, inhibited hyperalgesia caused by both agents, as did the knockdown of beta(1) integrin expression by intrathecal injection of antisense oligodeoxynucleotides. The laminin peptide, but not the fibronectin peptides, also reversibly abolished the longer lasting inflammatory hyperalgesia induced by carrageenan. Finally, the neuropathic hyperalgesia caused by systemic administration of the cancer chemotherapy agent taxol was reversibly inhibited by antisense knockdown of beta(1) integrin. These results strongly implicate specific integrins in the maintenance of inflammatory and neuropathic hyperalgesia.