Wake Forest University School of Medicine, Winston Salem, NC, USA.
Anesthesiology. 2012 Aug;117(2):389-98. doi: 10.1097/ALN.0b013e318260d381.
Monoaminergic pathways, impinging an α2-adrenoceptors and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions after neuropathic injury are unknown. Here we examine these interactions in rodents after nerve injury.
Male Sprague-Dawley rats following L5-L6 spinal nerve ligation (SNL) were used for either behavioral testing, in vivo microdialysis for γ-aminobutyric acid (GABA) and acetylcholine release, or synaptosome preparation for GABA release.
Intrathecal administration of the α2-adrenoceptor agonist (clonidine) and 5-HT3 receptor agonist (chlorophenylbiguanide) reduced hypersensitivity in SNL rats via GABA receptor-mediated mechanisms. Clonidine increased GABA and acetylcholine release in vivo in the spinal cord of SNL rats but not in normal rats. Clonidine-induced spinal GABA release in SNL rats was blocked by α2-adrenergic and nicotinic cholinergic antagonists. The 5-HT3 receptor antagonist ondansetron decreased and chlorophenylbiguanide increased spinal GABA release in both normal and SNL rats. In synaptosomes from the spinal dorsal horn of SNL rats, presynaptic GABA release was increased by nicotinic agonists and decreased by muscarinic and α2-adrenergic agonists. Spinally administered ondansetron significantly reduced clonidine-induced antihypersensitivity and spinal GABA release in SNL rats.
These results suggest that spinal GABA contributes to antihypersensitivity from intrathecal α2-adrenergic and 5-HT3 receptor agonists in the neuropathic pain state, that cholinergic neuroplasticity after nerve injury is critical for α2-adrenoceptor-mediated GABA release, and that blockade of spinal 5-HT3 receptors reduces α2-adrenoceptor-mediated antihypersensitivity via reducing total GABA release.
影响α2-肾上腺素能受体和 5-HT3 血清素受体的单胺能通路调节痛觉传递，但它们在神经损伤后的机制和相互作用尚不清楚。在这里，我们研究了这些在神经损伤后的啮齿动物中的相互作用。
雄性 Sprague-Dawley 大鼠在 L5-L6 脊神经结扎（SNL）后用于行为测试、体内微透析γ-氨基丁酸（GABA）和乙酰胆碱释放，或用于 GABA 释放的突触体制备。
鞘内给予α2-肾上腺素能受体激动剂（可乐定）和 5-HT3 受体激动剂（氯苯胍）通过 GABA 受体介导的机制减轻 SNL 大鼠的过敏反应。可乐定增加了 SNL 大鼠脊髓中的 GABA 和乙酰胆碱释放，但在正常大鼠中没有。SNL 大鼠脊髓中可乐定诱导的 GABA 释放被 α2-肾上腺素能和烟碱型胆碱能拮抗剂阻断。5-HT3 受体拮抗剂昂丹司琼减少并氯苯胍增加了正常和 SNL 大鼠的脊髓 GABA 释放。在 SNL 大鼠脊髓背角的突触体中，烟碱型激动剂增加了突触前 GABA 释放，而毒蕈碱型和 α2-肾上腺素能激动剂则减少了突触前 GABA 释放。鞘内给予昂丹司琼显著减少了 SNL 大鼠中氯定诱导的抗过敏反应和脊髓 GABA 释放。
这些结果表明，脊髓 GABA 有助于在神经病理性疼痛状态下鞘内给予α2-肾上腺素能和 5-HT3 受体激动剂的抗过敏反应，神经损伤后的胆碱能神经可塑性对于α2-肾上腺素能受体介导的 GABA 释放至关重要，并且阻断脊髓 5-HT3 受体通过减少总 GABA 释放来减少 α2-肾上腺素能受体介导的抗过敏反应。
