Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord.
Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord.
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DOI：
10.1016/j.bbi.2015.10.006
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Ji RR
中科院分区：
文献类型：
--
作者：
Taves S;Berta T;Liu DL;Gan S;Chen G;Kim YH;Van de Ven T;Laufer S;Ji RR
先前的研究表明，在各种啮齿动物模型中，脊髓小胶质细胞中p38丝裂原活化激酶（MAPK）的活化参与了炎症性疼痛和神经病理性疼痛的产生。然而，这些研究主要集中在雄性小鼠上，以避免雌性动情周期的混淆影响。最近的研究表明，一些脊髓促炎信号，如Toll样受体4介导的信号，有助于疼痛过敏性只在雄性小鼠。在这项研究中，我们研究了脊髓p38在炎症和神经病理性疼痛中的不同作用，使用高选择性p38抑制剂skepinone。鞘内注射skepinone预防福尔马林诱导的雄性小鼠炎性疼痛，但对雌性小鼠无效。此外，鞘内注射skepinone减少慢性压迫性损伤（CCI）诱导的神经性疼痛（机械异常性疼痛）在CCI-第7天，但不是CCI-第21天的雄性小鼠。鞘内注射skepinone后，这种对神经性疼痛的男性依赖性抑制也发生在大鼠中。在CCI-第7天，神经损伤诱导CX 3CR 1-GFP+小胶质细胞中脊髓p38活化（磷酸化），并且这种活化在雄性小鼠中更突出。相比之下，CCI在两种性别中诱导了相当的小胶质细胞增生和小胶质细胞标志物CX 3CR 1和IBA-1的表达。值得注意的是，腹膜内或局部神经周围给药的skepinone抑制CCI诱导的机械异常性疼痛在两种性别的小鼠。最后，skepinone只减少自发兴奋性突触后电流（sEPSC）的频率在板IIo神经元的脊髓切片CCI后7天的男性。因此，性别特异性p38激活和信号传导仅限于炎症和神经性疼痛条件下的脊髓。
Previous studies have shown that activation of p38 mitogen-activating kinase (MAPK) in spinal microglia participates in the generation of inflammatory and neuropathic pain in various rodent models. However, these studies focused on male mice to avoid confounding effects of the estrous cycle of females. Recent studies have shown that some spinal pro-inflammatory signaling such as Toll-like receptor 4-mediated signaling contributes to pain hypersensitivity only in male mice. In this study we investigated the distinct role of spinal p38 in inflammatory and neuropathic pain using a highly selective p38 inhibitor skepinone. Intrathecal injection of skepinone prevented formalin induced inflammatory pain in male but not female mice. Furthermore, intrathecal skepinone reduced chronic constriction injury (CCI) induced neuropathic pain (mechanical allodynia) in male mice on CCI-day 7 but not CCI-day 21. This male-dependent inhibition of neuropathic pain also occurred in rats following intrathecal skepinone. Nerve injury induced spinal p38 activation (phosphorylation) in CX3CR1-GFP+ microglia on CCI-day 7, and this activation was more prominent in male mice. In contrast, CCI induced comparable microgliosis and expression of the microglial markers CX3CR1 and IBA-1 in both sexes. Notably, intraperitoneal or local perineural administration of skepinone inhibited CCI-induced mechanical allodynia in both sexes of mice. Finally, skepinone only reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina IIo neurons of spinal cord slices of males 7 days post CCI. Therefore, the sex-specific p38 activation and signaling is confined to the spinal cord in inflammatory and neuropathic pain conditions.
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影响因子：
25
作者：
Ji, RR;Baba, H;Woolf, CJ
通讯作者：
Woolf, CJ
影响因子：
2.9
作者：
Cui, Y;Chen, Y;Chen, PX
通讯作者：
Chen, PX
DOI：
10.1073/pnas.0610811104
发表时间：
2007-06-19
影响因子：
11.1
作者：
Clark, Anna K.;Yip, Ping K.;Malcangio, Marzia
通讯作者：
Malcangio, Marzia
影响因子：
4.8
作者：
Bruce-Keller, AJ;Keeling, JL;Mattson, MP
通讯作者：
Mattson, MP
影响因子：
7.4
作者：
BENNETT, GJ;XIE, YK
通讯作者：
XIE, YK