Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin
Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin
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DOI：
10.1016/j.pain.2005.06.015
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发表时间：
2005-10-01
期刊：
影响因子：
7.4
通讯作者：
Dickenson, AH
中科院分区：
文献类型：
--
作者：
Suzuki, R;Rahman, W;Dickenson, AH
并不是所有的神经病理性疼痛患者都能从目前的治疗中得到缓解，其中包括被认为可以调节钙通道功能的抗惊厥剂加巴喷丁。我们报告了一个神经回路，这是允许加巴喷丁的有效性。用P物质-皂苷(SP-SAP)选择性地损毁表达P物质神经激肽-1受体的背角浅层神经元。逆行标记显示这些神经元投射到脑内，并参与脑干5-羟色胺能下行影响，通过易化5-羟色胺(3)受体来增强脊髓的兴奋性。我们发现，神经损伤后这一通路的完整性有助于行为异常痛、深背角神经元的神经元可塑性和加巴喷丁的损伤特异性作用。因此，SP-SAP减轻了脊神经结扎后的触觉和冷过敏以及神经元编码异常(包括自发活动、感受野大小扩大)。此外，加巴喷丁在神经病后的强大作用可通过消融表达NK-1的神经元或使用恩丹西酮拮抗5-羟色胺(3)受体来阻断。值得注意的是，5-羟色胺(3)受体的激活提供了一种状态依赖(独立于神经病变产生的依赖)，使得GBP在正常的未受伤动物中被强有力地抑制。因此，这个回路是神经病的异常神经和行为表现的关键决定因素，更重要的是，加巴喷丁的疗效。由于这种脊椎-延髓-脊髓环路接触到与疼痛的情感成分有关的大脑区域，这一环路可能代表了一种途径，通过这种途径，情绪可以影响患者的疼痛程度，以及药物治疗的效果。这些假说在患者身上是可检验的。(C)2005年国际疼痛研究协会。爱思唯尔出版，版权所有。
Not all neuropathic pain patients gain relief from current therapies that include the anticonvulsant, gabapentin, thought to modulate calcium channel function. We report a neural circuit that is permissive for the effectiveness of gabapentin. Substance P-saporin (SP-SAP) was used to selectively ablate superficial dorsal horn neurons expressing the neurokinin-1 receptor for substance P. These neurons project to the brain as shown by retrograde labelling and engage descending brainstem serotonergic influences that enhance spinal excitability via a facilitatory action on 5HT(3) receptors. We show the integrity of this pathway following nerve injury contributes to the behavioural allodynia, neuronal plasticity of deep dorsal horn neurons and the injury-specific actions of gabapentin. Thus SP-SAP attenuated the tactile and cold hypersensitivity and abnormal neuronal coding (including spontaneous activity, expansion of receptive field size) seen after spinal nerve ligation. Furthermore the powerful actions of gabapentin after neuropathy were blocked by either ablation of NK-1 expressing neurones or 5HT(3) receptor antagonism using ondansetron. Remarkably, 5HT(3) receptor activation provided a state-dependency (independent of that produced by neuropathy) allowing GBP to powerfully inhibit in normal uninjured animals. This circuit is therefore a crucial determinant of the abnormal neuronal and behavioural manifestations of neuropathy and importantly, the efficacy of gabapentin. As this spino-bulbo-spinal circuit contacts areas of the brain implicated in the affective components of pain, this loop may represent a route by which emotions can influence the degree of pain in a patient, as well as the effectiveness of the drug treatment. These hypotheses are testable in patients. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.