重复注射阿米替林可治疗神经性疼痛：调节去甲肾上腺素能下行抑制系统
本公众号每天分享一篇最新一期Anesthesia & Analgesia等SCI杂志的摘要翻译，敬请关注并提出宝贵意见
Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System
背景与目的
三环抗抑郁药阿米替林、5-羟色胺和去甲肾上腺素再摄取抑制剂度洛西汀和加巴沙星是用于治疗神经性疼痛的一线药物。这些药物的镇痛作用涉及脑干 - 脊髓下行去甲肾上腺素能系统。然而，并不清楚哪种阿米替林利用各种神经性疼痛镇痛机制中哪种是最重要的。在本研究中，我们研究了去甲肾上腺素能系统在这些药物治疗神经性疼痛中的作用。我们还检测了阿米替林是否能改变下行去甲肾上腺素能系统。
方 法
大鼠在L5脊髓神经结扎（SNL）7天后，给予N-（2-氯乙基）-N-乙基-2-溴苄胺（DSP-4,50mg / kg）使去甲肾上腺素能纤维退化。然后，从SNL手术后21天起，每天经腹膜内注射阿米替林（10mg / kg）、度洛西汀（10mg / kg）、普瑞巴林（10mg / kg）或加巴喷丁（50mg / kg））。用爪退缩阈值以评估药物对SNL后的痛觉过敏的影响。为了确定每天注射5次阿米替林是否可激活使用或不使用DSP-4治疗的脑脊液（LC）和脊髓中的去甲肾上腺素能神经元，我们采用c-Fos和多巴胺β羟化酶（DβH）的抗体进行免疫组织化学分析。
结 果
每日给SNL大鼠注射阿米替林、度洛西汀、普瑞巴林和加巴喷丁后发挥抗痛觉过敏作用（P <0.001;阿米替林[99％自信区间]的估计治疗效果：59.9 [35.1-84.7] g）。通过DSP-4预处理，度洛西汀、普瑞巴林和加巴喷丁的抗痛觉过敏作用逆转（分别为P <0.001）。然而，在用DSP-4预处理的SNL大鼠中注射阿米替林后仍然观察到抗痛觉过敏（P <0.001，59.7 [30.0-89.3] g）），并且这种止痛作用并不被α2-肾上腺素受体拮抗剂咪唑克生（30μg）逆转。另外，每日注射5次阿替曲林增加了使用或不使用DSP-4预处理的SNL大鼠中去甲肾上腺素能LC神经元中c-Fos免疫反应性（IR）细胞的比例（分别为P <0.001）。每日注射5次阿米替林可增加LC和SNL大鼠脊髓背角的DβH-IR（分别为P <0.001）。使用DSP-4预处理，每日注射或不注射5次阿米替林，DβH-IR都显著降低（P <0.001）。
结 论
尽管抑制去甲肾上腺素能下行抑制系统，但每日注射5次阿米替林可产生抗神经痛的抗痛觉反应。阿米替林激活了SNL大鼠的LC神经元并增加了去甲肾上腺素能的密度。这些结果表明阿米替林仍然可以在下行去甲肾上腺素能系统的病理功能障碍下产生镇痛作用。阿米替林可增强药物对神经性疼痛的镇痛作用，但这需要正常的下行去甲肾上腺素能抑制作用以产生镇痛药，如5-羟色胺和去甲肾上腺素再摄取抑制剂和加巴沙星。
原始文献摘要
Hiroki T, Suto T, Saito S, Obata H.Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System.Anesth Analg. 2017 Aug 4.
BACKGROUND:
The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drugs for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic systems. However, amitriptyline utilizes a variety of mechanisms for analgesia in neuropathic pain, and it is unclear which mechanism is most important. In the present study, we investigated the role of descending noradrenergic systems in the analgesic effect of these drugs for treatment of neuropathic pain. We also examined whether amitriptyline modifies the descendingnoradrenergic systems.
METHODS:
Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg) to degenerate noradrenergic fibers. The rats then received 5 daily intraperitoneal injections of amitriptyline (10 mg/kg), duloxetine (10 mg/kg), pregabalin (10 mg/kg), or gabapentin (50 mg/kg) from 21 days after SNL surgery. Paw withdrawal thresholds were determined to assess the effect of the drugs on hyperalgesia after SNL. To determine whether 5 daily injections of amitriptyline activated noradrenergic neurons in the locus coeruleus (LC) and spinal cord with or without DSP-4 treatment, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (DβH).
RESULTS:
Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P < .001; estimated treatment effect of amitriptyline [99% confidence interval]: 59.9 [35.1-84.7] g). The antihyperalgesic effects of duloxetine, pregabalin, and gabapentin were reversed by pretreatment with DSP-4 (P < .001, respectively). However, antihyperalgesia was still observed after treatment of amitriptyline in SNL rats with DSP-4 pretreatment (P < .001, 59.7 [30.0-89.3] g), and this analgesic effect was not reversed by the α2-adrenoceptor antagonist idazoxan (30 μg). Additionally, 5 daily injections of amitriptyline increased the ratio of c-Fos-immunoreactive (IR) cells in noradrenergic LC neurons in SNL rats with or without DSP-4 pretreatment (P < .001, respectively). Five daily injections of amitriptyline increased DβH-IR in the LC and the spinal dorsal horn of SNL rats (P < .001, respectively). With DSP-4 pretreatment, DβH-IR was dramatically decreased with or without 5 daily injections of amitriptyline (P < .001).
CONCLUSIONS:
Five daily injections of amitriptyline produced antihyperalgesic effects against neuropathic pain despite suppression of noradrenergic descending inhibitory systems. Amitriptyline activated LC neurons and increased noradrenergic fibers density in SNL rats. These results suggest that amitriptyline could still produce analgesia under pathological dysfunction of the descendingnoradrenergic system. Amitriptyline may enhance the analgesic effect of drugs for neuropathic pain that require normal descendingnoradrenergic inhibition to produce analgesia, such as serotonin and noradrenaline reuptake inhibitors and gabapentinoids.
麻醉学文献进展分享
联系我们