A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators
A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators
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DOI：
10.1523/jneurosci.5385-05.2006
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发表时间：
2006-04-05
影响因子：
5.3
通讯作者：
Levine, JD
中科院分区：
文献类型：
--
作者：
Alessandri-Haber, N;Dina, OA;Levine, JD
瞬时受体电位香草酸4（TRPV 4）是一种初级传入传导器，在渗透性和机械性刺激的神经性痛觉过敏以及渗透性刺激的炎症介质诱导的痛觉过敏中起着至关重要的作用。鉴于机械性痛觉过敏在炎症状态下的临床重要性，本研究探讨TRPV 4在炎症介质诱导的机械性痛觉过敏中的作用以及所涉及的第二信使途径。皮内注射致炎原角叉菜胶或炎性介质汤均能增强低渗或机械刺激引起的大鼠痛敏性缩足反射。脊髓注射TRPV 4反义寡核苷酸可阻断这种增强作用，而不改变基础伤害性阈值。类似地，在TRPV 4（-/-）敲除小鼠中，炎症汤未能诱导任何显著的机械或渗透性痛觉过敏。体外研究表明，炎症介质通过直接作用于分离的初级传入神经元来参与TRPV 4介导的致敏机制。额外的行为观察表明，多种介质是必要的，以实现足够的激活cAMP途径，从事TRPV 4依赖性机制的痛觉过敏。此外，直接激活蛋白激酶A或蛋白激酶C β（介导炎症诱导的机械性痛觉过敏的两种途径）也可诱导对低渗和机械刺激的痛觉过敏，而TRPV 4反义可降低这种痛觉过敏，并且在TRPV 4（-/-）小鼠中不存在。我们的结论是TRPV 4在机械性痛觉过敏中起着至关重要的作用，机械性痛觉过敏是由炎症组织中存在的炎症介质的协同作用产生的。
The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. Spinal administration of TRPV4 antisense oligodeoxynucleotide blocked the enhancement without altering baseline nociceptive threshold. Similarly, in TRPV4(-/-) knock-out mice, inflammatory soup failed to induce any significant mechanical or osmotic hyperalgesia. In vitro investigation showed that inflammatory mediators engage the TRPV4-mediated mechanism of sensitization by direct action on dissociated primary afferent neurons. Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C epsilon, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4(-/-) mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.