MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice.
MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice.
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DOI：
10.1016/j.neuroscience.2009.05.008
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发表时间：
2009-08-18
期刊：
影响因子：
3.3
通讯作者：
Firestein, G. S.
中科院分区：
文献类型：
--
作者：
Sorkin, L. S.;Boyle, D. L.;Hammaker, D.;Herman, D. S.;Vail, E.;Firestein, G. S.
脊髓p38 MAP激酶在慢性疼痛行为中起关键作用。然而，p38抑制剂的临床开发受到显著毒性的阻碍。为了评估p38调节的替代策略，我们确定了已知的p38上游激活剂（MKK 3和MKK 6）是否参与疼痛和脊髓p38磷酸化的发展和维持。急性疼痛行为在MKK 3或MKK 6缺陷小鼠中没有改变。MKK 3 −/−小鼠的2期福尔马林反应延迟，但幅度不变，而MKK 6 −/−小鼠的反应保持正常。更引人注目的是，晚期福尔马林异常性疼痛（注射后3至18天）在野生型和MKK 6 −/−小鼠中很突出，但在MKK 3 −/−小鼠中延迟了几天。在野生型小鼠中，而不是MKK 3 −/−小鼠中，足底福尔马林引起同侧脊髓MKK 3/6磷酸化的急性增加，并在注射后9天再次增加。MKK 3/6的磷酸化与2期福尔马林行为相关。野生型和MKK 3 −/−小鼠的脊髓磷酸化p38均表达增加，然而在WT小鼠中，这种反应早几天开始，并且比MKK 3 −/−小鼠的幅度和持续时间更高。这种磷酸化与晚期异常性疼痛相关。磷酸化的MKK 3/6仅在星形胶质细胞中检测到，鉴于P-p38通常在星形胶质细胞中看不到，这证明了影响小胶质细胞中p38磷酸化的可溶性介质的星形胶质细胞释放。综合这些数据，MKK 3而不是MKK 6是慢性疼痛行为和脊髓p38磷酸化的正常发展所必需的。
Spinal p38 MAP kinase plays a key role in chronic pain behavior. However, clinical development of p38 inhibitors has been hindered by significant toxicity. To evaluate alternative strategies of p38 regulation, we determined if known upstream activators of p38 (MKK3 and MKK6), are involved in development and maintenance of pain and spinal p38 phosphorylation. Acute pain behaviors were not altered in MKK3 or MKK6 deficient mice. The phase 2 formalin response was delayed in MKK3−/− mice, but unchanged in magnitude, while the response remained normal in MKK6−/− mice. More striking, late formalin allodynia (3 to 18 days post-injection) was prominent in wild type and MKK6−/− mice, but was delayed for several days in MKK3−/− mice. In wild type, but not MKK3−/− mice, intraplantar formalin elicited increases in ipsilateral spinal MKK3/6 phosphorylation acutely and again at 9 days post injection. Phosphorylation of MKK3/6 correlated with phase 2 formalin behavior. Wild type and MKK3−/− mice both expressed increases in spinal phosphorylated p38, however in WT mice this response began several days earlier, and was of higher magnitude and duration than in MKK3−/− mice. This phosphorylation correlated with the late allodynia. Phosphorylated MKK3/6 was detected only in astrocytes, given that P-p38 is usually not seen in astrocytes this argues for astrocytic release of soluble mediators that affect p38 phosphorylation in microglia. Taking these data together, MKK3, but not MKK6, is necessary for normal development of chronic pain behavior and phosphorylation of spinal p38.
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