Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.
Role of brainstem serotonin in analgesia produced by low-intensity exercise on neuropathic pain after sciatic nerve injury in mice.
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DOI：
10.1097/j.pain.0000000000000372
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发表时间：
2015-12
期刊：
影响因子：
7.4
通讯作者：
Santos ARS
中科院分区：
文献类型：
--
作者：
Bobinski F;Ferreira TAA;Córdova MM;Dombrowski PA;da Cunha C;Santo CCDE;Poli A;Pires RGW;Martins-Silva C;Sluka KA;Santos ARS
体育锻炼是减少人类神经性慢性疼痛的一种低成本、安全且有效的干预措施。然而，运动如何减轻神经性疼痛的根本机制尚不清楚。中枢单胺能系统在内源性镇痛中发挥着关键作用，这使我们推测低强度运动的镇痛作用是通过激活下行抑制系统中的单胺能神经传递而发生的。为了验证这一假设，我们通过挤压坐骨神经来诱导周围神经损伤（PNI）。运动干预包括受伤后立即在跑步机上进行两周的低强度跑步。患有 PNI 的动物表现出类似疼痛的行为增加，而在跑步机上跑步则减少了这种行为。使用色氨酸羟化酶抑制剂 PCPA 减少血清素 (5-HT) 合成会阻碍运动的镇痛效果。然而，用酪氨酸羟化酶抑制剂 AMPT 阻断儿茶酚胺合成却没有效果。与此同时，两周的运动增加了脑干 5-HT 及其代谢物 (5-HIAA) 的水平，降低了血清素转运蛋白 (SERT) 的表达，并增加了 5-HT 受体 (5HT-1B、2A、2C) 的表达。最后，PNI 诱导的脑干炎症细胞因子 TNF-α 和 IL-1β 的增加通过 2 周的运动得以逆转。这些发现提供了新的证据，表明低强度有氧跑步机运动通过增强脑干 5-HT 神经传递来抑制神经性疼痛动物的疼痛样行为。这些数据为运动产生的镇痛提供了理论依据，为治疗慢性神经性疼痛提供了另一种方法。
Physical exercise is a low-cost, safe and efficient intervention for the reduction of neuropathic chronic pain in humans. However, the underlying mechanisms for how exercise reduces neuropathic pain are not yet well understood. Central monoaminergic systems play a critical role in endogenous analgesia leading us to hypothesize that the analgesic effect of low-intensity exercise occurs through activation of monoaminergic neurotransmission in descending inhibitory systems. To test this hypothesis we induced peripheral nerve injury (PNI) by crushing the sciatic nerve. The exercise intervention consisted of low-intensity treadmill running for two weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-HT) synthesis using the tryptophan hydroxylase inhibitor PCPA prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor AMPT had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-HIAA), decreased expression of the serotonin transporter (SERT), and increased expression of 5-HT receptors (5HT-1B, 2A, 2C). Lastly, PNI-induced increased in inflammatory cytokines, TNF-α and IL-1β, in the brainstem was reversed by 2 weeks of exercise. These findings provide new evidence indicating that low-intensity aerobic treadmill exercise suppresses pain-like behaviors in animals with neuropathic pain by enhancing brainstem 5-HT neurotransmission. These data provide a rationale for the analgesia produced by exercise to provide an alternative approach to the treatment of chronic neuropathic pain.