Background and Goal of Study: The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drug for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic (NA) systems. In the present study, we investigated the difference in NA dependency of each drug. We also examined whether amitriptyline modifies the descending NA systems. 
Materials and 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 NA fibers. The rats then received five 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 analgesic effect of the drugs by paw pressure test. To determine whether five daily injections of amitriptyline activated NA neurons in the locus coeruleus (LC) and spinal cord, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (DβH).
Results and Discussion: Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P< 0.001). The antihyperalgesic effects of duloxetine, pregabalin, and gabapentin were reversed by pretreatment with DSP-4 (P< 0.001). However, antihyperalgesia was still observed after treatment of amitriptyline in SNL rats with DSP-4 pretreatment, and this analgesic effect was not reversed by the α2-adrenoceptor antagonist idazoxan (30 µg). Additionally, amitriptyline increased the ratio of c-Fos-immunoreactive (IR) cells in noradrenergic LC neurons in SNL rats with or without DSP-4 pretreatment (P< 0.001). Amitriptyline increased DβH-IR in the LC and the spinal dorsal horn of SNL rats (P< 0.001). However, in DSP-4 pretreated groups, amitriptyline did not increase DβH-IR in both tissue (P< 0.001).
Conclusion(s): Five daily injections of amitriptyline produced antihyperalgesic effects against neuropathic pain despite the condition that NA descending inhibitory systems are suppressed. Amitriptyline could still produce analgesia under pathological dysfunction of the descending NA system. In patients with neuropathic pain, amitriptyline may enhance the analgesic effects of drugs that require descending NA inhibitory systems, such as duloxetine and gabapentinoids.

Effects of repeated administration of amitriptyline on modulation of noradrenergic descending inhibitory system in a rat model of neuropathic pain