From the *Department of Anesthesiology, Gunma University Graduate School of Medicine, Gunma, Japan; †Center of Pain Management, Fukushima Medical University Hospital, Fukushima, Japan; and ‡Department of Anesthesiology, Fukushima Medical University, Fukushima, Japan.
Anesth Analg. 2017 Oct;125(4):1281-1288. doi: 10.1213/ANE.0000000000002352.
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.
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).
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).
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.
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西汀和加巴喷丁类药物是治疗神经病理性疼痛的一线药物。这些药物的镇痛作用与脑干脊髓下行去甲肾上腺素能系统有关。然而，阿米替林利用多种机制治疗神经病理性疼痛，其镇痛机制尚不清楚。在本研究中，我们研究了下行去甲肾上腺素能系统在这些药物治疗神经病理性疼痛中的镇痛作用。我们还研究了阿米替林是否会改变下行去甲肾上腺素能系统。
在 L5 脊神经结扎（SNL）后 7 天，大鼠接受 N-（2-氯乙基）-N-乙基-2-溴苯甲胺（DSP-4，50mg/kg）以使去甲肾上腺素能纤维变性。然后，大鼠从 SNL 手术后 21 天开始每天接受 5 次腹腔注射阿米替林（10mg/kg）、度洛西汀（10mg/kg）、普瑞巴林（10mg/kg）或加巴喷丁（50mg/kg）。通过测定 paw withdrawal thresholds 来评估药物对 SNL 后痛觉过敏的影响。为了确定 5 天的阿米替林注射是否激活了有或没有 DSP-4 治疗的蓝斑核（LC）和脊髓中的去甲肾上腺素能神经元，我们使用 c-Fos 和多巴胺 β-羟化酶（DβH）抗体进行免疫组织化学。
5 天的阿米替林、度洛西汀、普瑞巴林和加巴喷丁治疗对 SNL 大鼠有抗痛觉过敏作用（P <.001；阿米替林的估计治疗效果[99%置信区间]：59.9[35.1-84.7]g）。度洛西汀、普瑞巴林和加巴喷丁的抗痛觉过敏作用在 DSP-4 预处理时被逆转（分别为 P <.001）。然而，在 SNL 大鼠中用 DSP-4 预处理后，仍观察到阿米替林的抗痛觉过敏作用（P <.001，59.7[30.0-89.3]g），α2-肾上腺素能受体拮抗剂 idazoxan（30μg）并不能逆转这种镇痛作用。此外，5 天的阿米替林注射增加了有或没有 DSP-4 预处理的 SNL 大鼠中蓝斑核去甲肾上腺素能神经元中 c-Fos-免疫反应性（IR）细胞的比例（P <.001，分别）。5 天的阿米替林注射增加了 SNL 大鼠 LC 和脊髓背角的 DβH-IR（P <.001，分别）。在 DSP-4 预处理时，有或没有 5 天的阿米替林注射，DβH-IR 明显减少（P <.001）。
尽管抑制了去甲肾上腺素能下行抑制系统，5 天的阿米替林注射仍对神经病理性疼痛产生抗痛觉过敏作用。阿米替林激活了 LC 神经元并增加了 SNL 大鼠中去甲肾上腺素能纤维的密度。这些结果表明，在下行去甲肾上腺素能系统发生病理性功能障碍的情况下，阿米替林仍能产生镇痛作用。阿米替林可能会增强需要正常下行去甲肾上腺素能抑制作用来产生镇痛作用的治疗神经病理性疼痛的药物的镇痛效果，如 5-羟色胺和去甲肾上腺素再摄取抑制剂和加巴喷丁类药物。
