Abstract 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.

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1 型大麻素受体及其作为镇痛剂的作用：阿片类药物的替代品？

摘要 了解身体如何调节疼痛对于制定合理的策略来对抗日益流行的慢性疼痛状态、阿片类药物依赖和医疗保健系统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突出原因，大量文献已经确定了内源性大麻素通路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状况（急性、炎症、慢性和神经性）中过度的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，其镇痛特性已被充分证明；然而，了解大麻素疼痛调节存在主要障碍。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药物副作用的存在，这严重阻碍了它们的使用。这种剂量限制作用阻止了适当程度的镇痛。动物研究表明，精神作用是通过脑大麻素 1 (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。开发适当的疗法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。近期生理、药理、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/或谷氨酸盐的释放。本文将在其对疼痛的影响的背景下审查该证据。我们首先简要概述了 CB1R 在调节伤害感受中的作用，然后回顾了外周内源性大麻素系统调节伤害感受的证据。然后我们详细研究了中枢介导的镇痛的调节，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中 GABA 能和谷氨酸能神经传递的调节。最后，我们讨论了在炎症和神经元直接调节的背景下大麻素对非神经元细胞的作用。