Hayashida Ken-ichiro, Parker Renée, Eisenach James C
Department of Anesthesiology and Center for Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1009, USA.
Anesthesiology. 2007 Jun;106(6):1213-9. doi: 10.1097/01.anes.0000267605.40258.98.
Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil.
Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design.
Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine.
Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.
向小鼠脑内注射加巴喷丁可减轻神经损伤诱导的超敏反应，鞘内注射阿托品可阻断该作用，而鞘内注射新斯的明可增强此作用。作者通过研究口服加巴喷丁对大鼠神经损伤后超敏反应的减轻效果及其与临床使用的胆碱酯酶抑制剂多奈哌齐的相互作用，来检验这些发现与口服治疗的相关性。
对脊髓神经结扎后出现超敏反应的雄性大鼠，分别经口服、鞘内注射和脑室内注射加巴喷丁，同时或不同时鞘内注射阿托品，测定 paw 压力的撤药阈值。采用等效应线图设计，确定单独及联合使用口服加巴喷丁和多奈哌齐对撤药阈值的影响。
加巴喷丁通过所有给药途径均可减轻对 paw 压力的超敏反应，脑室内注射比鞘内注射更有效且起效更快。鞘内注射阿托品可逆转脑室内注射和口服加巴喷丁的作用。口服加巴喷丁和多奈哌齐以强烈的协同方式相互作用，观察到的疗效为相加作用预测剂量的十分之一。鞘内注射阿托品可逆转加巴喷丁 - 多奈哌齐的联合作用。
尽管加巴喷丁可能通过在多个部位的作用来缓解神经性疼痛，但这些结果表明，口服给药后其在脑内引起脊髓胆碱能激活的作用占主导。副作用，尤其是恶心，在大鼠身上无法准确确定。然而，口服多奈哌齐在治疗阿尔茨海默病痴呆患者时耐受性良好，本研究为加巴喷丁和多奈哌齐联合治疗神经性疼痛的临床研究提供了理论依据。
