Opiorphin的稳定类似物STR-324通过激活内源性阿片受体依赖通路引起术后疼痛的镇痛

P. Sitbon, A. C. Elstraete, Leila Hamdi, V. Juárez-Pérez, J. Mazoit, D. Benhamou, C. Rougeot
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引用次数: 2

摘要

Opiorphin是一种天然的人肽,具有很强的镇痛作用。这些镇痛作用被认为导致脑啡肽水解减少,继发于脑啡肽酶的复合抑制。这项研究的目的是证明opiorphin及其稳定的类似物STR-324是有希望的镇痛药,可能是寻求一种新的有效而安全的止痛药的解决方案。脑啡肽分解抑制剂可能是一类长效止痛药,具有比直接阿片受体激动剂更好的安全性。虽然opiorphin和STR-324在术后疼痛模型中的疗效尚未确定,但在大鼠切口疼痛模型中,opiorphin和STR-324均通过阿片受体介导的机制降低机械超敏反应,且无不良心肺作用。采用布伦南足底切口致超敏反应模型,观察连续静脉注药7 d大鼠术后对机械和热刺激的镇痛反应,每组8 ~ 10只(机械组和热组)。将opiorphin与吗啡和STR-324的抗痫作用进行比较,并特异性研究脊髓c-Fos的表达和阿片受体依赖通路的作用。还进行了测试以评估opiorphin对呼吸和血流动力学的不良影响。结果发现,术后第1 ~ 4天静脉注射opiorphin显著降低机械刺激反应,平均范围为143 ~ 175 kpa,而对照组平均范围为23 ~ 30 kpa (P < 0.05)。在此期间,opiorphin未引起呼吸频率、血氧饱和度、动脉压或心率的不良反应。STR-324反复表现出对机械和热痛觉过敏的抑制作用,其效力与opiorphin相似。STR-324显著减少了免疫染色后可识别的疼痛引起的脊髓c-Fos免疫反应核的数量。通过机制分析,也证明了阿片拮抗剂纳洛酮逆转了STR-324的抗伤害性作用。综上所述,术后静脉注射opiorphin和STR-324具有明显的抗伤害性作用
本文章由计算机程序翻译,如有差异,请以英文原文为准。
STR-324, a Stable Analog of Opiorphin, Causes Analgesia in Postoperative Pain by Activating Endogenous Opioid Receptor-dependent Pathways
Opiorphin is a natural human peptide with strong analgesic properties. These analgesic effects thought to result in a reduction in enkephalin hydrolysis secondary to the compound inhibition of enkephalinase. The purpose of this study was to demonstrate that opiorphin and its stable analog STR-324 are promising analgesics that may be the solution to the quest for a new class of effective, yet safe, painkillers. Inhibitors of enkephalin breakdown could potentially be a class of longacting painkillers with a better safety profile than direct opioid receptor agonists. Although their efficacy in postoperative pain models has not been established, both opiorphin and STR-324 reduced mechanical hypersensitivity through opioid receptor–mediated mechanisms without adverse cardiorespiratory effects in a rat incisional pain model. The demonstrationwas done via the Brennanmodel of plantar incision–induced hypersensitivity with examination of the postsurgical analgesic response to mechanical and thermal stimuli in rats with 7 days of continuously intravenously infused drugs There were a total of 8 to 10 rats per group (mechanical and thermal). Antinociception caused by opiorphin was compared with that of morphine and STR-324, and the expression of spinal c-Fos and the role of opioid receptor–dependent pathways were specifically targeted. Tests were also conducted to assess any manifestation of adverse respiratory and hemodynamic effects with opiorphin. It was found that intravenously administered opiorphin infusion significantly decreased responses to mechanical stimuli postsurgery from days 1 to 4 at 143to 175-kPa mean ranges compared with 23to 30-kPa mean ranges for vehicle (P < 0.05). During this period, no adverse effects in respiratory rate, oxygen saturation, arterial pressure, or heart rate were induced by opiorphin. STR-324 repeatedly demonstrated inhibition of mechanical and thermal hyperalgesia with a potency similar to that of opiorphin. STR-324 significantly reduced the number of pain-evoked spinal c-Fos immunoreactive nuclei that could be identified after immunostaining. Through the use of mechanistic analyses, it was also demonstrated that the opioid antagonist naloxone reversed the antinociceptive effect of STR-324. In conclusion, a significant antinociceptive effect of intravenous opiorphin and STR-324 was demonstrated in a postoperative
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