TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain.
TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain.
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DOI：
10.1523/jneurosci.4288-08.2009
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发表时间：
2009-04-29
期刊：
影响因子：
--
通讯作者：
Basbaum AI
中科院分区：
文献类型：
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作者：
Wang X;Ratnam J;Zou B;England PM;Basbaum AI
初级传入伤害感受器的激活会产生急性、短暂的疼痛，组织或神经损伤会导致伤害感受处理的长期增强，表现为对热和机械刺激的超敏反应。在这里，我们使用化学遗传学和药理学方法来研究受体酪氨酸激酶（TrkB）对损伤引起的持续性疼痛的产生和维持的贡献。我们在表达突变但功能齐全的 TrkB 受体的野生型小鼠和转基因 (TrkBF616A) 小鼠中进行了研究。通过注射蛋白激酶抑制剂蛋白磷酸酶1（1NM-PP1）的小分子衍生物，可以在成年小鼠中产生对TrkB自磷酸化的高度选择性抑制，而不干扰其他蛋白激酶的活性。我们报告说，口服 1NM-PP1（以阻断脊髓中 TrkB 磷酸化的剂量）对急性热、机械或化学疼痛敏感性的行为测试没有影响。然而，使用 1NM-PP1 进行相同的预处理可防止组织或神经损伤引起的热和机械过敏的发生。腹腔注射 1NM-PP1 可暂时逆转已建立的超敏反应。尽管干扰 TrkB 信号传导既不会改变急性辣椒素也不会改变福尔马林诱导的疼痛行为，但通过 1NM-PP1 抑制 TrkB 信号传导可以防止这些化学损伤产生的长期机械超敏反应。我们得出的结论是，TrkB 信号传导不仅是诱导组织或神经损伤产生的热和机械超敏反应的重要因素，而且也是疼痛持续存在的重要因素。
Activation of primary afferent nociceptors produces acute, short-lived pain, and tissue or nerve injury induces long-term enhancement of nociceptive processing, manifested as hypersensitivity to thermal and mechanical stimulation. Here we used a chemical-genetic and pharmacological approach to study the contribution of the receptor tyrosine kinase (TrkB) to the generation and maintenance of injury-induced persistent pain. We performed the studies in wild type mice and transgenic (TrkBF616A) mice that express mutant, but fully functional TrkB receptors. By injecting a small molecule derivative of the protein kinase inhibitor, protein phosphatase 1 (1NM-PP1), it is possible to produce highly selective inhibition of TrkB autophosphorylation in adult mice, without interfering with the activity of other protein kinases. We report that oral administration of 1NM-PP1, at doses that blocked phosphorylation of TrkB in the spinal cord, had no effect in behavioral tests of acute heat, mechanical or chemical pain sensitivity. However, the same pretreatment with 1NM-PP1 prevented the development of tissue- or nerve injury-induced heat and mechanical hypersensitivity. Established hypersensitivity was transiently reversed by intraperitoneal injection of 1NM-PP1. Although interfering with TrkB signaling altered neither acute capsaicin nor formalin-induced pain behavior, the prolonged mechanical hypersensitivity produced by these chemical injuries was prevented by 1NM-PP1 inhibition of TrkB signaling. We conclude that TrkB signaling is not only an important contributor to the induction of heat and mechanical hypersensitivity produced by tissue or nerve injury, but also to the persistence of the pain.