Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Anesthesiology. 2012 Jun;116(6):1347-53. doi: 10.1097/ALN.0b013e318254e6fd.
Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, the authors tested whether gabapentin reduced γ-amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord.
Male Sprague-Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used. Immunostaining for glutamic acid decarboxylase and GABA release in synaptosomes and microdialysates were examined in the LC and spinal dorsal horn.
Basal GABA release and expression of glutamic acid decarboxylase increased in the LC but decreased in the spinal dorsal horn after SNL. In microdialysates from the LC, intravenously administered gabapentin decreased extracellular GABA concentration in normal and SNL rats. In synaptosomes prepared from the LC, gabapentin and other α2δ ligands inhibited KCl-evoked GABA release in normal and SNL rats. In microdialysates from the spinal dorsal horn, intravenous gabapentin did not alter GABA concentrations in normal rats but slightly increased them in SNL rats. In synaptosomes from the spinal dorsal horn, neither gabapentin nor other α2δ ligands affected KCl-evoked GABA release in normal and SNL rats.
These results suggest that peripheral nerve injury induces plasticity of GABAergic neurons differently in the LC and spinal dorsal horn and that gabapentin reduces presynaptic GABA release in the LC but not in the spinal dorsal horn. The current study supports the idea that gabapentin activates descending noradrenergic inhibition via disinhibition of LC neurons.
加巴喷丁可减轻急性术后和慢性神经病理性疼痛，但作用部位和机制尚不清楚。基于先前的电生理研究，作者检测了加巴喷丁是否通过减少蓝斑（LC）中γ-氨基丁酸（GABA）的释放来发挥作用，LC 是下行抑制的主要部位，而不是在脊髓中。
使用雄性 Sprague-Dawley 大鼠进行实验，这些大鼠接受或不接受 L5-L6 脊神经结扎（SNL）。在 LC 和脊髓背角中检测谷氨酸脱羧酶和突触小体及微透析液中 GABA 释放的免疫染色。
SNL 后，LC 中 GABA 释放和谷氨酸脱羧酶的表达增加，而脊髓背角中则减少。在 LC 微透析液中，静脉给予加巴喷丁可降低正常和 SNL 大鼠的细胞外 GABA 浓度。在 LC 制备的突触小体中，加巴喷丁和其他 α2δ 配体抑制正常和 SNL 大鼠 KCl 诱导的 GABA 释放。在脊髓背角微透析液中，静脉内给予加巴喷丁不会改变正常大鼠的 GABA 浓度，但会轻微增加 SNL 大鼠的 GABA 浓度。在脊髓背角的突触小体中，加巴喷丁和其他 α2δ 配体均不影响正常和 SNL 大鼠 KCl 诱导的 GABA 释放。
这些结果表明，周围神经损伤导致 LC 和脊髓背角中的 GABA 能神经元产生不同的可塑性，加巴喷丁减少 LC 中的突触前 GABA 释放，但不影响脊髓背角中的 GABA 释放。本研究支持加巴喷丁通过抑制 LC 神经元的去抑制作用激活下行去甲肾上腺素能抑制的观点。
