Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?
Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?
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DOI：
10.1080/15504263.2019.1668100
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发表时间：
2019-10-07
影响因子：
2.2
通讯作者：
Burton, Michael D.
中科院分区：
文献类型：
--
作者：
Milligan, Amber L.;Szabo-Pardi, Thomas A.;Burton, Michael D.
了解身体如何调节疼痛对于制定合理的策略来应对日益流行的慢性疼痛状态、阿片类药物依赖以及医疗保健系统日益增加的经济负担至关重要。疼痛是美国人寻求医疗救助的最主要原因，大量文献已经确定了内源性大麻素途径在控制疼痛方面的重要性。内源性大麻素系统的调节为选择性控制多种疼痛（急性、炎症、慢性和神经性疼痛）中的过度神经元活动提供了新的治疗机会。大麻素具有悠久的药用历史，其镇痛特性已有详细记录。然而，了解大麻素疼痛调节存在重大障碍。一个主要问题是与 D9-四氢大麻酚 (THC) 或合成衍生物相关的精神副作用的存在，这极大地限制了它们的使用。这种剂量限制效应阻碍了适当程度的镇痛。动物研究表明，精神作用是通过大脑 1 型大麻素 (CB1) 受体介导的，而慢性疼痛状态下的镇痛活性可能是通过脊髓、脑干、外周感觉神经元或免疫细胞中的 CB1R 作用介导的。适当疗法的开发有赖于我们对外周与中枢内源性大麻素驱动镇痛作用的理解。最近的生理学、药理学和解剖学研究提供的证据表明，内源性大麻素系统的主要作用之一是调节γ-氨基丁酸（GABA）和/或谷氨酸的释放。本文将回顾这一证据对疼痛的影响。我们首先简要概述 CB1R 在伤害感受调节中的作用，然后回顾外周内源性大麻素系统调节伤害感受的证据。然后，我们详细研究中枢介导的镇痛调节，随后有证据表明大麻素介导的疼痛调节涉及关键大脑区域的 GABA 能和谷氨酸能神经传递的调节。最后，我们讨论了大麻素在炎症和神经元直接调节背景下对非神经元细胞的作用。这项工作揭示了大麻素镇痛领域长期存在的争议，这些争议对失败的临床试验和针对该系统的治疗的实施产生了影响。
Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia . Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R?s role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoidmediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.