The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.
The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.
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DOI：
10.1016/j.pain.2009.11.017
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发表时间：
2010-02
期刊：
影响因子：
7.4
通讯作者：
Ji RR
中科院分区：
文献类型：
--
作者：
Gao YJ;Xu ZZ;Liu YC;Wen YR;Decosterd I;Ji RR
外周炎症诱导持续的中枢敏感化，其特征在于由不同机制介导的机械异常性疼痛和热痛觉过敏。与热痛觉过敏的机制相比，机械性异常性疼痛和对侧疼痛的机制还不完全清楚。在这项研究中，我们研究了脊髓JNK在炎性疼痛模型中热痛觉过敏、机械异常性疼痛和对侧疼痛中的不同作用。足底注射完全弗氏佐剂（CFA）诱导双侧机械性痛觉超敏，但单侧热痛觉过敏。CFA还诱导脊髓中JNK的双侧活化（磷酸化），并且磷酸化JNK 1（pJNK 1）水平远高于pJNK 2。值得注意的是，pJNK和JNK 1都在GFAP阳性星形胶质细胞中表达。鞘内注射选择性JNK肽抑制剂D-JNKI-1，在炎症前通过渗透泵开始，在维持阶段减少CFA诱导的机械异常性疼痛，但对CFA诱导的热痛觉过敏没有影响。鞘内推注D-JNKI-1或SP 600126（JNK的小分子抑制剂）也可逆转双侧机械性异常性疼痛。相比之下，外周（足底）施用D-JNKI-1减少CFA诱导的热痛觉过敏的诱导，但不改变机械性异常性疼痛。最后，CFA诱导的双侧机械性异常性疼痛在缺乏JNK 1但不缺乏JNK 2的小鼠中减弱。总之，我们的数据表明，脊髓JNK，特别是JNK 1在维持持续性炎症性疼痛中起着重要作用。我们的研究结果还揭示了JNK 1和星形胶质细胞网络在调节触觉异常性疼痛和对侧疼痛中的独特作用。
Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund’s adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.
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