Departments of Medicine and Oral Surgery and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143.
Departments of Medicine and Oral Surgery and Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143
J Neurosci. 2019 Sep 4;39(36):7061-7073. doi: 10.1523/JNEUROSCI.1191-19.2019. Epub 2019 Jul 12.
Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, , subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E (PGE) hyperalgesia. OIH was reversed, , by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nm) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a μ-opioid receptor (MOR)-dependent increase in [Ca] in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4 and IB4 neurons. This sensitizing effect of fentanyl was reversed in weakly IB4 DRG neurons cultured from opioid-primed rats after treatment with cordycepin, to reverse of OIH. Thus, administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. Clinically used μ-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid-naive and opioid-primed animals, and provide evidence for the important role of nociceptor μ-opioid receptor-mediated calcium signaling and peripheral protein translation in the weakly IB4-binding population of nociceptors in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.
阿片类药物诱导的痛觉过敏（OIH）是阿片类镇痛药引起的一种严重不良反应。缺乏合适的模型阻碍了对其潜在机制的研究。最近的证据表明伤害感受器在 OIH 中起作用。为了研究伤害感受器中 OIH 的细胞和分子机制，本文作者皮下给予芬太尼（30μg/kg，s.c.）的镇痛剂量，在雄性大鼠中进行。两天后，当芬太尼经皮内（1μg，i.d.）给药时，在周围伤害感受器末梢附近，它会产生机械性痛觉过敏（OIH）。此外，在全身给予芬太尼 2 天后，大鼠还出现了痛觉过敏引发（阿片类药物引发的大鼠），即持久的伤害感受器神经可塑性表现为前列腺素 E（PGE）痛觉过敏延长。鞘内给予虫草素（一种逆转引发的蛋白翻译抑制剂）逆转了 OIH。当芬太尼（0.5nm）应用于来自阿片类药物引发的大鼠的背根神经节（DRG）神经元时，它诱导小直径神经元中 26%的μ-阿片受体（MOR）依赖性[Ca]增加，并显著敏化（降低动作电位阈值）弱 IB4 和 IB4 神经元。虫草素处理后，来自阿片类药物引发的大鼠的弱 IB4 DRG 神经元中，芬太尼的这种敏化作用被逆转，OIH 也被逆转。因此，芬太尼的给药诱导伤害感受器神经可塑性，这种可塑性在培养中持续存在，为伤害感受器 MOR 介导的钙信号和外周蛋白翻译在弱 IB4 结合伤害感受器群体中在 OIH 中的作用提供了证据。临床上使用的μ-阿片受体激动剂，如芬太尼，可产生痛觉过敏和痛觉过敏引发。本文作者报告了一种伤害感受器神经可塑性模型，该模型介导了芬太尼引起的这种阿片类药物诱导的痛觉过敏（OIH）和引发。使用该模型，本文作者发现了来自阿片类药物未处理和阿片类药物引发的动物的培养伤害感受器之间的定性和定量差异，并为伤害感受器 μ-阿片受体介导的钙信号和外周蛋白翻译在弱 IB4 结合伤害感受器群体中在 OIH 中的重要作用提供了证据。这些发现为设计减轻 OIH 的治疗策略提供了有用的信息，OIH 是阿片类镇痛药的一种严重不良反应。
