低剂量吗啡对人类和大鼠痛觉感受器的敏化作用依赖于 TLR4。

IF 2.8 3区 医学 Q2 NEUROSCIENCES
Eugen V Khomula, Dionéia Araldi, Paul G Green, Jon D Levine
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引用次数: 0

摘要

虽然阿片类药物仍然是治疗中度至重度疼痛的最有效疗法之一,但其巨大的副作用仍然是临床广泛使用的主要限制因素。其中一种副作用是阿片类药物诱导的超痛感(OIH),包括从阿片类药物诱导的镇痛到疼痛增强的转变。啮齿类动物的证据支持这样一种观点,即 OIH 可能是阿片类药物通过 Toll 样受体 4(TLR4)作用于免疫细胞而产生的,免疫细胞反过来又会产生前感觉介质作用于痛觉感受器,或者是通过直接作用于痛觉感受器 TLR4 而产生的。而且,亚镇痛剂量的几种阿片类药物已被证明可通过其作为 TLR4 激动剂的作用诱发啮齿动物的超痛觉。在目前的体外贴片钳电生理学实验中,我们证明了低剂量吗啡能直接敏化人类和啮齿类动物的背根神经节(DRG)神经元,这种阿片类镇痛药的效应能被选择性 TLR4 拮抗剂 LPS-RS Ultrapure 所拮抗。我们发现,低浓度(100 nM)吗啡会降低人(36%)和大鼠(26%)假定的 C 型痛觉感受器的流变基,而吗啡的这种效应在与 LPS-RS Ultrapure 预孵育后会明显减弱。我们的研究结果支持这样一种观点,即在人类和啮齿类动物中,OIH 是由阿片类药物在 TLR4 上对痛觉感受器的直接作用介导的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sensitization of human and rat nociceptors by low dose morphine is toll-like receptor 4-dependent.

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that low concentration (100 nM) of morphine reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.

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来源期刊
Molecular Pain
Molecular Pain 医学-神经科学
CiteScore
5.60
自引率
3.00%
发文量
56
审稿时长
6-12 weeks
期刊介绍: Molecular Pain is a peer-reviewed, open access journal that considers manuscripts in pain research at the cellular, subcellular and molecular levels. Molecular Pain provides a forum for molecular pain scientists to communicate their research findings in a targeted manner to others in this important and growing field.
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