Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus.
Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus.
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DOI：
10.1097/j.pain.0000000000000608
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发表时间：
2016-09
期刊：
影响因子：
7.4
通讯作者：
Hayashida KI
中科院分区：
文献类型：
--
作者：
Kimura M;Eisenach JC;Hayashida KI
尽管加巴喷丁是慢性神经性疼痛的首选镇痛药之一，但它有时不能提供镇痛作用，但其缺乏疗效的机制尚不清楚。包括L5-L6脊髓神经结扎（SNL）在内的神经损伤大鼠对加巴喷丁的反应一致且良好，但许多研究都是在损伤后几周内进行的，质疑它们与慢性神经性疼痛的相关性。在这项研究中，腹腔注射加巴喷丁显示SNL后抗超敏反应的时间依赖性降低，这与蓝斑（LC）星形胶质谷氨酸转运蛋白-1 （GLT-1）的下调有关。一致地，SNL也具有时间依赖性，增加了加巴喷丁诱导的LC中基础但隐蔽的去肾上腺素能神经元活性。在SNL后2周的大鼠中，LC中GLT-1的敲低降低了加巴喷丁的抗过敏作用。在SNL后8周的大鼠中，组蛋白去乙酰化酶抑制剂丙戊酸增加GLT-1的表达恢复了加巴喷丁的抗过敏作用，与恢复加巴喷丁诱导的LC中去甲肾上腺素能神经元活性和随后的脊髓去甲肾上腺素释放有关。LC中GLT-1的敲低逆转了丙戊酸恢复加巴喷丁诱导的抗超敏反应的作用。此外，鞘内2-肾上腺素能受体激动剂clonidine的抗超敏作用也随SNL损伤后时间的延长而减弱。这些结果表明，LC中GLT-1的下调和脊髓去甲肾上腺素能抑制的减弱导致加巴喷丁对慢性神经性疼痛的镇痛效果受损，丙戊酸盐可以挽救这种受损的疗效。
Despite being one of the first-choice analgesics for chronic neuropathic pain, gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve ligation (SNL) respond uniformly and well to gabapentin, but many of these studies are performed within just a few weeks of injury, questioning their relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin showed a time-dependently reduction in antihypersensitivity after SNL, associated with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus coeruleus (LC). Consistently, SNL also time-dependently increased basal but masked gabapentin-induced noradrenergic neuronal activity in the LC. In rats 2 weeks after SNL, knock-down of GLT-1 in the LC reduced the antihypersensitivity effect of gabapentin. In rats 8 weeks after SNL, increasing GLT-1 expression by histone deacetylase inhibitor valproate restored the antihypersensitivity effect of gabapentin, associated with restored gabapentin-induced noradrenergic neuronal activity in the LC and subsequent spinal noradrenaline release. Knock-down of GLT-1 in the LC reversed the effect of valproate to restore gabapentin-induced antihypersensitivity. In addition, the antihypersensitivity effect of the intrathecal a2-adrenoceptor agonist clonidine also decreased with time after SNL injury. These results suggest that downregulation of GLT-1 in the LC and reduced spinal noradrenergic inhibition contribute to impaired analgesic efficacy from gabapentin in chronic neuropathic pain and that valproate can rescue this impaired efficacy.