Spinal alpha 2-adrenoceptor-mediated analgesia in neuropathic pain reflects brain-derived nerve growth factor and changes in spinal cholinergic neuronal function.
Spinal alpha 2-adrenoceptor-mediated analgesia in neuropathic pain reflects brain-derived nerve growth factor and changes in spinal cholinergic neuronal function.
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DOI：
10.1097/aln.0b013e3181de6d2c
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发表时间：
2010-08
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;Eisenach JC
脊髓α2-肾上腺素能受体刺激在神经性疼痛状态下产生镇痛作用，这种作用在动物中被脑源性神经营养因子（BDNF）功能抑制剂阻断。在大鼠中，α2-肾上腺素能受体的刺激通常抑制乙酰胆碱的释放，但在神经损伤后使乙酰胆碱的释放兴奋。我们研究了BDNF和兴奋性Gs蛋白在这一变化中的作用。雄性大鼠行L5-L6脊髓神经结扎术（SNL），腰脊背角灌注或不灌注BDNF，用于乙酰胆碱释放突触体制备或胆碱乙酰转移酶免疫染色。SNL不改变突触体的自发释放或脊髓背角胆碱乙酰转移酶的免疫反应性，但降低了kcl引起的乙酰胆碱释放。右美托咪定抑制正常大鼠突触小体中kcl诱发的乙酰胆碱释放，但刺激SNL大鼠突触小体中kcl诱发的乙酰胆碱释放，这两种作用均被α2肾上腺素受体拮抗剂咪唑嗪阻断。脊髓输注BDNF抗体降低了正常和SNL大鼠脊髓背角胆碱乙酰转移酶的免疫反应性，并消除了右美托咪定对kcl诱导的SNL大鼠乙酰胆碱释放的促进作用。右美托咪定对乙酰胆碱释放的促进作用也被Gs功能抑制剂阻断。脊髓α - 2肾上腺素能受体对胆碱能刺激的依赖性增加，引起神经损伤后的镇痛，部分反映了脊髓胆碱能神经元从直接抑制到直接兴奋的转变。我们的研究结果表明，这种转变依赖于与Gs蛋白和BDNF的相互作用。
Spinal α2-adrenoceptor stimulation produces analgesia in neuropathic pain states, and this effect in animals is blocked by inhibitors of brain derived neurotrophic factor (BDNF) function. In rats, α2-adrenoceptor stimulation normally inhibits acetylcholine release, but excites release after nerve injury. We examined the roles of BDNF and excitatory Gs protein in this change. Male rats underwent L5-L6 spinal nerve ligation (SNL) and their lumbar spinal dorsal horns with or without spinal BDNF infusion were used for either synaptosome preparation for acetylcholine release or immunostaining for choline acetyltransferase. SNL did not alter spontaneous release from synaptosomes or choline acetyltransferase-immunoreactivity in the spinal dorsal horn, but reduced KCl-evoked acetylcholine release. Dexmedetomidine inhibited KCl-evoked acetylcholine release in synaptosomes from normal rats, but excited KCl-evoked release in synaptosomes from SNL rats, and both effects were blocked by the α2-adrenoceptor antagonist, idazoxan. Spinal infusion of an antibody to BDNF reduced choline acetyltransferase-immunoreactivity in the spinal dorsal horn in both normal and SNL rats, and abolished facilitation of KCl-evoked acetylcholine release by dexmedetomidine in SNL rats. Dexmedetomidine’s facilitation of acetylcholine release was also blocked by inhibitors of Gs function. The increased reliance of spinal α2-adrenoceptors on cholinergic stimulation to cause analgesia after nerve injury reflects in part a shift from direct inhibition to direct excitation of spinal cholinergic neurons. Our results suggest this shift relies on an interaction with Gs proteins and BDNF.