TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization.
TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization.
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DOI：
10.1523/jneurosci.0893-09.2009
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发表时间：
2009-05-13
期刊：
影响因子：
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通讯作者：
Levine JD
中科院分区：
文献类型：
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作者：
Alessandri-Haber N;Dina OA;Chen X;Levine JD
瞬时受体电位香草酸 4 (TRPV4) 会导致多种病因的机械痛觉过敏，可能是机械感受器信号复合体的一部分。为了研究 TRPV4 和拉伸激活离子通道 (SAC) 之间的功能性相互作用参与这种机械转导机制的假设，我们使用了选择性 SAC 抑制剂 GsMTx-4。在大鼠后爪皮内注射 GsMTx-4 可逆转皮内注射炎症介质引起的机械痛觉过敏。体内单纤维记录显示，GsMTx-4 逆转了一半致敏 C 纤维中炎症介质诱导的机械阈值降低。此外，GsMTx-4 可减少不同炎症和神经性疼痛模型中机械和低渗刺激的痛觉过敏，但对基线机械伤害性阈值没有影响。 TRPC1 和 TRPC6 是两种 GsMTx-4 敏感的 SAC，在背根神经节神经元 (DRG) 中表达。单细胞 RT-PCR 显示 TRPV4、TRPC1 和 TRPC6 的信使 RNA 经常在 DRG 神经元中共表达。脊髓鞘内注射 TRPC1 和 TRPC6 的反义寡脱氧核苷酸（如 TRPV4 的反义寡脱氧核苷酸），逆转了炎症介质诱导的机械和低渗刺激的痛觉过敏，而不影响基线机械伤害性阈值。然而，TRPC6 反义而非 TRPC1 反义可逆转由热损伤或 TRPV4 选择性激动剂 4α-PDD 引起的机械痛觉过敏。我们得出结论，TRPC1 和 TRPC6 通道与 TRPV4 通道配合介导机械痛觉过敏和初级传入伤害感受器敏化，尽管它们可能具有独特的作用。
The transient receptor potential vanilloid 4 (TRPV4) contributes to mechanical hyperalgesia of diverse etiologies, presumably as part of a mechanoreceptor signaling complex. To investigate the hypothesis that a functional interaction between TRPV4 and stretch-activated ion channels (SACs) is involved in this mechanical transduction mechanism, we used a selective SACs inhibitor, GsMTx-4. Intradermal injection of GsMTx-4 in the rat hind paw reversed the mechanical hyperalgesia induced by intradermal injection of inflammatory mediators. In vivo single fiber recordings showed that GsMTx-4 reversed inflammatory mediator-induced decrease in mechanical threshold in half of sensitized C-fibers. Furthermore, GsMTx-4 reduced hyperalgesia to both mechanical and hypotonic stimuli in different models of inflammatory and neuropathic pain while it had no effect on baseline mechanical nociceptive thresholds. TRPC1 and TRPC6, two GsMTx-4-sensitive SACs are expressed in dorsal root ganglion neurons (DRG). Single-cell RT-PCR showed that messenger RNAs for TRPV4, TRPC1 and TRPC6 are frequently co-expressed in DRG neurons. Spinal intrathecal administration of oligodeoxynucleotides antisense to TRPC1 and TRPC6, like that to TRPV4, reversed the hyperalgesia to mechanical and hypotonic stimuli induced by inflammatory mediators without affecting baseline mechanical nociceptive threshold. However, antisense to TRPC6, but not to TRPC1, reversed the mechanical hyperalgesia induced by a thermal injury or the TRPV4 selective agonist 4α-PDD. We conclude that TRPC1 and TRPC6 channels cooperate with TRPV4 channels to mediate mechanical hyperalgesia and primary afferent nociceptor sensitization although they may have distinctive roles.