Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats
Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats
复制标题
DOI：
10.1213/ane.0000000000001301
复制
发表时间：
2016-08-01
影响因子：
5.7
通讯作者：
Obata, Hideaki
中科院分区：
文献类型：
--
作者：
Matsuoka, Hiroaki;Suto, Takashi;Obata, Hideaki
背景：有害刺激诱导的镇痛（NSIA）是大鼠的一种条件疼痛调节，已被用于评估内源性疼痛控制系统。去甲肾上腺素能下降系统参与NSIA，神经损伤引起去甲肾上腺素能下降神经元的可塑性改变。因此，我们假设神经损伤会影响NSIA的强度，而阿米替林和普瑞巴林（常用于治疗神经性疼痛）可能通过影响降去甲肾上腺素能系统进一步调节NSIA。方法：通过测量左前爪辣椒素注射后对侧后爪戒断阈值，观察大鼠右L5脊髓神经结扎术后NSIA随时间的变化。此外，我们检查了每天腹腔注射阿米替林或普瑞巴林5次后的NSIA。在未损伤大鼠、SNL大鼠和每天腹腔注射阿米替林或普瑞巴林5次的SNL大鼠左前爪辣椒素后，采用微透析研究测量左脊髓背角左前爪辣椒素注射后去甲肾上腺素水平。结果：NSIA在SNL后5、6周显著减弱（P < 0.001）。前爪注射辣椒素的非损伤大鼠腰椎脊髓的非肾上腺素水平与载药注射相比显著升高（P < 0.001），但在SNL手术后6周的大鼠中无明显升高。在SNL后5周，每日5次腹腔注射阿米替林（10 mg/kg/d）或普瑞巴林（10 mg/kg/d）逐渐增加同侧后肢戒断阈值（P < 0.001）。在SNL后6周，阿米替林而非普瑞巴林逆转了SNL对NSIA的减弱（P < 0.001），并增加了前爪注射辣椒素后脊髓去甲肾上腺素水平（P = 0.005）。结论：这些数据提示神经性疼痛状态下的内源性镇痛在神经损伤后一定时间内明显减弱，阿米替林通过影响降甲肾上腺素能系统逆转内源性镇痛的减弱。
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 nor-adrenaline 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.