Gabapentin Acts within the Locus Coeruleus to Alleviate Neuropathic Pain
Gabapentin Acts within the Locus Coeruleus to Alleviate Neuropathic Pain
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DOI：
10.1097/aln.0b013e31818dac9c
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发表时间：
2008-12-01
期刊：
影响因子：
8.8
通讯作者：
Eisenach, James C.
中科院分区：
文献类型：
--
作者：
Hayashida, Ken-ichiro;Obata, Hideaki;Eisenach, James C.
背景：加巴喷丁在神经损伤后招募下行抑制来产生镇痛，但这是否是脑干的局部作用尚不清楚。作者假设加巴喷丁通过局部作用激活蓝斑 (LC) 中的去甲肾上腺素能神经元。方法：男性。大鼠接受 L5-L6 脊神经结扎 (SNL)，并通过 LC 内或全身途径接受药物，以进行行为测试、LC 中的免疫组织化学以及脊髓背角的微透析。在其他研究中，使用正常动物和 SNL 动物的脑干切片进行免疫组织化学分析。结果：SNL 增加了 LC 中双侧磷酸化环磷酸腺苷反应元件结合蛋白 (I)CREB) 表达的核，并增加了脊髓背角中去甲肾上腺素的释放。加巴喷丁，无论是在分离的脑干切片中，还是在清醒或麻醉的动物中，都会增加LC中表达pCREB的细胞核。加巴喷丁引起的pCREB表达的净增加在正常和SNL条件下没有差异。 AMPA 受体拮抗剂 6-cyano-7-硝基喹喔啉-2,3-二酮 (CNQX) 消除了加巴喷丁在 LC 神经元中诱导的 pCREB 激活。 LC 内注射加巴喷丁以剂量依赖性方式降低 SNL 大鼠的超敏反应。 LC 内联合给予 CNQX 和鞘内给予 α(2)-肾上腺素受体拮抗剂伊达唑生均可阻断 LC 内加巴喷丁的抗过敏作用。静脉;加巴喷丁诱导脊髓背角去甲肾上腺素释放。与正常情况相比，SNL 大鼠中加巴喷丁释放的去甲肾上腺素净量较多，尽管相对于基线的增加百分比相同。结论：这些结果表明，加巴喷丁通过谷氨酸依赖性机制直接作用于脑干，刺激下行抑制，在周围神经损伤后产生抗过敏作用。
Background: Gabapentin recruits descending inhibition to produce analgesia after nerve injury, but whether this is a local action in the brainstem is unknown. The authors hypothesized that gabapentin activates noradrenergic neurons in the locus coeruleus (LC) by a local action.Methods: Male. rats underwent L5-L6 spinal nerve ligation (SNL) and received drugs by intra-LC or systemic routes for behavior testing, immunohistochemistry in die LC, and microdialysis in the spinal dorsal horn. In other studies, brainstem slices from normal and SNL animals were used for immunohistochemistry.Results: SNL increased phosphorylated cyclic adenosine monophosphate response element binding protein (I)CREB)expressing nuclei bilaterally in the LC, and increased noradrenaline release in the spinal dorsal horn. Gabapentin, whether in isolated brainstem slices or in conscious or anesthetized animals, increased pCREB-expressing nuclei in the LC The net increase in pCREB expression by gabapentin did not differ between normal and SNL conditions. This gabapentin-induced pCREB activation in LC neurons was abolished by an AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Intra-LC-injected gabapentin reduced hypersensitivity in SNL rats in a dose-dependent manner. Both intra-LC coadministration of CNQX and intrathecal administration of the alpha(2)-adrenoceptor antagonist idazoxan blocked antihypersensitivity by intra-LC gabapentin. intravenous; gabapentin induced noradrenaline release in die spinal dorsal horn. The net amount of noradrenaline release by gabapentin is larger in SNL rats compared with the normal condition, although the percentage increases from the baseline were the same.Conclusions: These results suggest that gabapentin acts directly in the brainstem via a glutamate-dependent mechanism to stimulate descending inhibition to produce antihypersensitivity after peripheral nerve injury.