Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation.
Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation.
复制标题
DOI：
10.1016/j.neuroscience.2016.03.032
复制
发表时间：
2016-06-02
期刊：
影响因子：
3.3
通讯作者：
Levine JD
中科院分区：
文献类型：
--
作者：
Ferrari LF;Araldi D;Bogen O;Levine JD
我们提出细胞外基质向透明质酸受体 CD44 发出信号，以增加对机械刺激的反应性。我们报告皮内注射透明质酸酶会诱导机械性痛觉过敏，而这种现象可通过同时给予 CD44 受体拮抗剂 A5G27 来抑制。皮内注射低分子量 (LMWH) 但非高分子量 (HMWH) 透明质酸也会诱发机械痛觉过敏，这种效应会因 HMWH 或 A5G27 预处理而减弱。 HMWH 预处理还可以减弱透明质酸酶引起的痛觉过敏。同样，皮内注射 A6（一种 CD44 受体激动剂）会产生痛觉过敏，而这种痛觉过敏可被 HMWH 和 A5G27 抑制。蛋白激酶 A 和 Src 抑制剂（但不是蛋白激酶 C）显着减弱 A6 和 LMWH 引起的痛觉过敏。最后，为了确定 CD44 受体信号传导是否参与炎症性疼痛的临床前模型，我们评估了 A5G27 和 HMWH 对与角叉菜胶诱导的炎症相关的机械痛觉过敏的影响。 A5G27 和 HMWH 均减弱角叉菜胶诱导的机械痛觉过敏。因此，LMWH 作用于其同源受体 CD44 来诱导机械痛觉过敏，而 HMWH 作为拮抗剂作用于同一受体。 HMWH 或 A5G27 的局部给药可抑制角叉菜胶诱导的痛觉过敏，这支持了角叉菜胶引起细胞外基质变化从而导致炎性疼痛的观点。这些研究定义了透明质酸受体 CD44 信号传导在增加对机械刺激的反应性方面的临床相关作用。
We propose that the extracellular matrix signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by the pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A and Src, but not protein kinase C, significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the extracellular matrix that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation.