Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System
Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System
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DOI：
10.1213/ane.0000000000002352
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发表时间：
2017-10-01
影响因子：
5.7
通讯作者：
Obata, Hideaki
中科院分区：
文献类型：
--
作者：
Hiroki, Tadanao;Suto, Takashi;Obata, Hideaki
背景技术背景：三环类抗抑郁药阿米替林、5-羟色胺和去甲肾上腺素再摄取抑制剂度洛沙汀和加巴喷丁是治疗神经性疼痛的一线药物。这些药物的镇痛作用与脑干-脊髓降肾上腺素能系统有关。然而，阿米替林利用多种机制用于神经性疼痛的镇痛，并且尚不清楚哪种机制是最重要的。在本研究中，我们研究了降肾上腺素能系统在这些药物治疗神经病理性疼痛的镇痛作用中的作用。我们还研究了阿米替林是否修改下行去甲肾上腺素能system.METHODS：7天后L5脊神经结扎（SNL），大鼠接受N-（2-氯乙基）N-乙基-2-bronnobenzylannine（DSP-4，50 mg/kg）退化去甲肾上腺素能纤维。然后，从SNL手术后21天开始，大鼠每天接受5次阿米替林（10 mg/kg）、度洛沙汀（10 mg/kg）、普瑞巴林（10 mg/kg）或加巴喷丁（50 mg/kg）的腹膜内注射。测定缩爪阈值以评估药物对SNL后痛觉过敏的影响。为了确定5天一次注射阿米替林是否激活蓝斑（LC）和脊髓中的去甲肾上腺素能神经元（有或没有DSP-4处理），我们使用c-Fos和多巴胺β-羟化酶抗体进行免疫组织化学结果：阿米替林、度洛沙汀、普瑞巴林和加巴喷丁每天5次注射对SNL大鼠产生抗痛觉过敏作用（P <0.001;阿米替林的估计治疗效果[99%置信区间]：59.9 [35.1-84.7] g）。DSP-4预处理可逆转度洛西汀、普瑞巴林和加巴喷丁的抗痛觉过敏作用（分别为P <0.001）。然而，在用DSP-4预处理的SNL大鼠中，阿米替林治疗后仍观察到抗痛觉过敏（P <0.001，59.7 [30.0-89.3] g），并且这种镇痛作用不被α 2-肾上腺素受体拮抗剂咪唑克生（30 μ g）逆转。此外，每天注射5次阿米替林可增加SNL大鼠去甲肾上腺素能LC神经元中c-Fos免疫反应（IR）细胞的比例（分别为P <0.001）。阿米替林每日注射5次可增加SNL大鼠LC和脊髓背角的D β H-IR（分别为P <0.001）。DSP-4预处理后，无论是否每天注射5次阿米替林，D β H-IR均显著降低（P <0.001）。结论：尽管去甲肾上腺素能下行抑制系统受到抑制，但每天注射5次阿米替林对神经病理性疼痛产生抗痛觉过敏作用。阿米替林激活SNL大鼠LC神经元，增加去甲肾上腺素能纤维密度。提示阿米替林在去甲肾上腺素能系统病理性功能障碍的情况下仍能产生镇痛作用。阿米替林可增强神经性疼痛药物的镇痛作用，这些药物需要正常的下行去甲肾上腺素能抑制来产生镇痛作用，如5-羟色胺和去甲肾上腺素再摄取抑制剂和加巴喷丁类。
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 descending noradrenergic systems.METHODS: Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)N-ethyl-2-bronnobenzylannine (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 (D beta H).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 alpha 2-adrenoceptor antagonist idazoxan (30 mu g). 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 D beta H-IR in the LC and the spinal dorsal horn of SNL rats (P < .001, respectively). With DSP-4 pretreatment, D beta H-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 descending noradrenergic system. Amitriptyline may enhance the analgesic effect of drugs for neuropathic pain that require normal descending noradrenergic inhibition to produce analgesia, such as serotonin and noradrenaline reuptake inhibitors and gabapentinoids.