Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of γ-aminobutyric acid in α2-adrenoceptor and 5-HT3 serotonin receptor analgesia.
Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of γ-aminobutyric acid in α2-adrenoceptor and 5-HT3 serotonin receptor analgesia.
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DOI：
10.1097/aln.0b013e318260d381
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发表时间：
2012-08
期刊：
影响因子：
8.8
通讯作者：
Eisenach JC
中科院分区：
文献类型：
--
作者：
Hayashida K;Kimura M;Yoshizumi M;Hobo S;Obata H;Eisenach JC
单胺能通路，冲击α2-肾上腺素受体和5-HT 3-羟色胺受体，调节伤害性传递，但其机制和神经病理性损伤后的相互作用尚不清楚。在这里，我们研究这些相互作用在啮齿动物神经损伤后。将L5-L 6脊神经结扎（SNL）后的雄性Sprague-Dawley大鼠用于行为测试、用于γ-氨基丁酸（GABA）和乙酰胆碱释放的体内微透析或用于GABA释放的突触体制备。鞘内注射α2-肾上腺素受体激动剂（可乐定）和5-HT 3受体激动剂（氯苯基双胍）通过GABA受体介导的机制降低SNL大鼠的超敏反应。可乐定能增加SNL大鼠脊髓GABA和乙酰胆碱的释放，但对正常大鼠无明显影响。α2-肾上腺素能和烟碱胆碱能拮抗剂可阻断可乐定诱导的SNL大鼠脊髓GABA释放。5-HT_3受体拮抗剂昂丹司琼减少正常和SNL大鼠脊髓GABA释放，氯苯双胍增加脊髓GABA释放。在SNL大鼠脊髓背角突触体中，突触前GABA释放被烟碱激动剂增加，而被毒蕈碱和α2-肾上腺素能激动剂减少。脊髓给药昂丹司琼显着减少可乐定诱导的抗过敏和脊髓GABA释放在SNL大鼠。这些结果表明，脊髓GABA有助于神经病理性疼痛状态下鞘内α2-肾上腺素能和5-HT 3受体激动剂的抗超敏反应，神经损伤后胆碱能神经可塑性对α2-肾上腺素能受体介导的GABA释放至关重要，脊髓5-HT 3受体的阻断通过减少总GABA释放来减少α2-肾上腺素能受体介导的抗超敏反应。
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-amino butyric 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, pre-synaptic GABA release was increased by nicotinic agonists and decreased by muscarinic and α2-adrenergic agonists. Spinally administered ondansetron significantly reduced clonidine-induced anti-hypersensitivity and spinal GABA release in SNL rats. These results suggest that spinal GABA contributes to anti-hypersensitivity 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 anti-hypersensitivity via reducing total GABA release.