阿米替林而非普瑞巴林可逆转大鼠神经损伤后伤害性刺激诱导镇痛作用的减弱。

Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats.

作者信息

Matsuoka Hiroaki, Suto Takashi, Saito Shigeru, Obata Hideaki

机构信息

From the Department of Anesthesiology, Gunma University Graduate School of Medicine, Gunma, Japan.

出版信息

Anesth Analg. 2016 Aug;123(2):504-10. doi: 10.1213/ANE.0000000000001301.

DOI:10.1213/ANE.0000000000001301

PMID:27088996

Abstract

BACKGROUND

Noxious stimulus-induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system.

METHODS

We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin.

RESULTS

NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005).

CONCLUSIONS

These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

摘要

背景

伤害性刺激诱导的镇痛（NSIA）是大鼠一种条件性疼痛调制类型，已被用于评估内源性疼痛控制系统。下行去甲肾上腺素能系统参与NSIA，并且神经损伤会引起下行去甲肾上腺素能神经元的可塑性变化。因此，我们假设神经损伤会影响NSIA强度，并且常用于治疗神经性疼痛的阿米替林和普瑞巴林可能通过对下行去甲肾上腺素能系统的作用进一步调节NSIA。

方法

我们通过测量左前爪注射辣椒素后对侧后爪的缩足阈值，研究大鼠右侧L5脊神经结扎（SNL）后NSIA随时间的变化。此外，我们在连续5天腹腔注射阿米替林或普瑞巴林后检测NSIA。进行微透析研究以测量未受伤大鼠、SNL大鼠以及连续5天腹腔注射阿米替林或普瑞巴林的SNL大鼠左前爪注射辣椒素后左脊髓背角的去甲肾上腺素水平。

结果

SNL后5周和6周，NSIA显著减弱（P < 0.001）。与注射赋形剂相比，接受前爪注射辣椒素的未受伤大鼠腰脊髓中的去甲肾上腺素水平显著升高（P < 0.001），但SNL手术后6周的大鼠中未升高。SNL后5周连续5天腹腔注射阿米替林（10 mg/kg/d）或普瑞巴林（10 mg/kg/d）逐渐增加同侧后爪缩足阈值（P < 0.001）。SNL后6周，阿米替林而非普瑞巴林逆转了SNL对NSIA的减弱作用（P < 0.001），并增加了前爪注射辣椒素后的脊髓去甲肾上腺素水平（P = 0.005）。