Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-33, Showa, Maebashi, Gunma 371-8511, Japan.
Neurosci Lett. 2012 Oct 31;529(1):70-4. doi: 10.1016/j.neulet.2012.08.008. Epub 2012 Aug 16.
The activation of α2-adrenoceptors has attracted attention as a therapeutic target for neuropathic pain, which remains a clinical challenge. In the present study, we examined the interaction between α2-adrenergic and cholinergic signaling in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intrathecal administration of dexmedetomidine, which is a selective α2-adrenoceptor agonist (0.1-1.0 μg), dose-dependently suppressed hyperalgesia in SNL rats but did not alter paw withdrawal thresholds in normal rats. The analgesic effect of dexmedetomidine was abolished by intrathecal pretreatment with idazoxan (30 μg) and atropine (30 μg), which antagonize the α2-adrenoreceptor and muscarinic receptor, respectively. In vivo microdialysis in the lumbar spinal dorsal horn revealed that acetylcholine concentrations increased after dexmedetomidine perfusion (1 μM), but only in SNL rats. The combination of an ineffective dose of intrathecal dexmedetomidine with intraperitoneal donepezil, which is a cholinesterase inhibitor, decreased neuropathic hypersensitivity. These results suggest that plasticity of the spinal noradrenergic-cholinergic axis only occurs in neuropathic pain states. Thus, drug combinations that strengthen the noradrenergic-cholinergic interaction may provide therapeutic benefit in neuropathic pain.
α2-肾上腺素受体的激活已成为治疗神经性疼痛的一个治疗靶点，而神经性疼痛仍然是一个临床挑战。在本研究中，我们研究了在由脊神经结扎（SNL）引起的神经性疼痛大鼠模型中，α2-肾上腺素能和胆碱能信号之间的相互作用。鞘内给予右美托咪定，一种选择性α2-肾上腺素受体激动剂（0.1-1.0 μg），剂量依赖性地抑制 SNL 大鼠的痛觉过敏，但不改变正常大鼠的足底撤回阈值。鞘内预先给予伊达唑兰（30 μg）和阿托品（30 μg）可消除右美托咪定的镇痛作用，伊达唑兰和阿托品分别拮抗α2-肾上腺素受体和毒蕈碱受体。在腰椎脊髓背角的活体微透析中发现，右美托咪定灌注后（1 μM）乙酰胆碱浓度增加，但仅在 SNL 大鼠中增加。鞘内给予无效剂量的右美托咪定与腹腔内多奈哌齐（一种胆碱酯酶抑制剂）联合使用，可降低神经性痛觉过敏。这些结果表明，脊髓去甲肾上腺素能-胆碱能轴的可塑性仅在神经性疼痛状态下发生。因此，增强去甲肾上腺素能-胆碱能相互作用的药物联合可能为神经性疼痛提供治疗益处。
