Wang Chang-Lin, Yang Dai-Jun, Yuan Bi-Yu, Qiu Ting-Ting
From the School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
Anesth Analg. 2017 Dec;125(6):2123-2133. doi: 10.1213/ANE.0000000000002318.
The spared nerve injury (SNI) model is a new animal model that can mimic several characteristics of clinical neuropathic pain. Opioids are recommended as treatment of neuropathic pain. Therefore, the present study was conducted to investigate the antinociceptive effects of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) given centrally and peripherally in the SNI model of neuropathic pain in mice.
The SNI model was made in mice by sparing the sural nerve intact, when the other 2 of 3 terminal branches of the sciatic nerve (common peroneal and tibial nerves) were tightly ligated and cut. Von Frey monofilaments were used to measure the SNI-induced mechanical allodynia-like behavior. The antiallodynic effects of EM-1 and EM-2 were determined after central and peripheral administration in the SNI model of neuropathic pain. Also, the specific opioid receptor antagonists were used to determine the opioid mechanisms of EMs involved in neuropathic pain. Values were expressed as the mean ± standard deviation.
Our results showed that the SNI mice developed prolonged mechanical allodynia-like behavior in ipsilateral paw after surgery, with the withdrawal threshold value being 0.061 ± 0.02 g after 14 days. EM-1 and EM-2 produced significant antiallodynic effects in ipsilateral paw after intracerebroventricular (i.c.v.) administration, more effective than that of morphine. The peak withdrawal thresholds of 10 nmol EM-1 and EM-2 determined at 5 minutes after injection were 0.92 ± 0.36 and 0.87 ± 0.33 g, respectively, higher than that of morphine (0.46 ± 0.20 g). Moreover, both EMs (10 nmol, i.c.v.) exerted significant antiallodynic effects in the contralateral paw, whereas no significant antinociceptive activity was seen after i.c.v. administration of morphine with equimolar dose. It was noteworthy that EM-1 and EM-2 produced antinociception through distinct μ1- and μ2-opioid receptor subtypes, and the EM-2-induced antiallodynia contained an additional component that was mediated by the release of endogenous dynorphin A, acting on κ-opioid receptor. In addition, the antiallodynic activities of peripheral administration of EM-1, EM-2, and morphine were also investigated. Intraplantar, but not subcutaneous administration of EM-1 and EM-2 also exhibited potent antinociception, establishing the peripheral and local effects. Both μ1- and μ2-opioid receptor subtypes, but not the δ- or κ-opioid receptors were involved in the peripheral antiallodynia of EMs.
The present investigation demonstrated that both EM-1 and EM-2 given centrally and peripherally produced potent antiallodynic activities in SNI mice, and differential opioid mechanisms were involved.
保留神经损伤（SNI）模型是一种新的动物模型，可模拟临床神经性疼痛的多种特征。阿片类药物被推荐用于治疗神经性疼痛。因此，本研究旨在探讨在小鼠神经性疼痛的SNI模型中，中枢和外周给予内吗啡肽-1（EM-1）和内吗啡肽-2（EM-2）的镇痛作用。
通过保留腓肠神经完整，将坐骨神经的3个终末分支中的另外2个（腓总神经和胫神经）紧密结扎并切断，在小鼠中建立SNI模型。使用von Frey细丝测量SNI诱导的机械性异常性疼痛样行为。在神经性疼痛的SNI模型中，中枢和外周给药后，测定EM-1和EM-2的抗痛觉过敏作用。此外，使用特异性阿片受体拮抗剂确定EMs参与神经性疼痛的阿片类机制。数值以平均值±标准差表示。
我们的结果表明，SNI小鼠术后同侧爪出现延长的机械性异常性疼痛样行为，14天后的撤针阈值为0.061±0.02 g。脑室注射（i.c.v.）EM-1和EM-2后，同侧爪产生显著的抗痛觉过敏作用，比吗啡更有效。注射后5分钟测定的10 nmol EM-1和EM-2的峰值撤针阈值分别为0.92±0.36和0.87±0.33 g，高于吗啡（0.46±0.20 g）。此外，两种EMs（10 nmol，i.c.v.）在对侧爪均发挥显著的抗痛觉过敏作用，而等摩尔剂量的吗啡脑室注射后未观察到显著的镇痛活性。值得注意的是，EM-1和EM-2通过不同的μ1和μ2阿片受体亚型产生镇痛作用，EM-2诱导的抗痛觉过敏还包含由内源性强啡肽A释放介导的额外成分，作用于κ阿片受体。此外，还研究了外周给予EM-1、EM-2和吗啡的抗痛觉过敏活性。足底注射而非皮下注射EM-1和EM-2也表现出强效镇痛作用，证实了外周和局部作用。μ1和μ2阿片受体亚型均参与了EMs的外周抗痛觉过敏作用，而δ或κ阿片受体未参与。
本研究表明，中枢和外周给予EM-1和EM-2均可在SNI小鼠中产生强效的抗痛觉过敏活性，且涉及不同的阿片类机制。
