Therapeutic and Mechanistic Evaluation of Cannabis sativa Terpenes in Neuropathic Pain

大麻萜烯治疗神经性疼痛的治疗和机制评价

基本信息

批准号：
10441501
负责人：
John Michael Streicher
金额：
$ 32.03万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441501
关键词：
Acute Pain Adenosine Affect Agonist American Analgesics Anti-Inflammatory Agents Basic Science Biological Models Brain CNR1 gene CNR2 gene CRISPR/Cas technology Cannabidiol Cannabinoids Cannabis Cannabis sativa plant Chemotherapy-induced peripheral neuropathy Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Complex Mixtures Consumption Crude Extracts Development Diabetes Mellitus Diabetic Neuropathies Dose Epidemic Evaluation Genes Gold Health Human In Vitro Inflammation Inhalation Investigation Ligands Literature Measures Methods Modeling Molecular Morphine Neuropathy Nociception Opiate Addiction Opioid Oral Overdose Pain Pain management Patients Persons Pharmaceutical Preparations Pharmacology Pharmacopoeias Plants Production Property Quality of life Receptor Activation Research Rewards Role Route Sample Size Site Spinal Cord Tail Terpenes Testing Tetrahydrocannabinol Therapeutic Therapeutic Effect Time Tissues Translational Research United States Ventilatory Depression Work addiction addiction liability animal pain antagonist chemotherapy chronic pain conditioned place preference cytokine drug development economic cost improved in vitro Model in vivo Model insight linalool mouse model nerve injury non-cannabinoid non-opioid analgesic opioid abuse opioid epidemic opioid overdose pain model pain patient pain relief painful neuropathy phytocannabinoid preclinical study prevent research clinical testing response side effect standard care synergism

项目摘要

ABSTRACT Chronic pain is a serious and worsening epidemic in the United States and worldwide, seriously degrading patient quality of life. Opioid drugs like morphine are the “gold standard” for treating moderate to severe chronic pain, however, they are burdened by major side effects, especially addiction liability, which has contributed to a paralell epidemic of opioid addiction, abuse, and overdose. In addition, opioids are ineffective in some pain types, most notably neuropathic pain. In the search for alternatives, phytocannabinoids from Cannabis sativa have been heavily studied. However, cannabinoids have generally been shown to have modest to poor efficacy, and have their own side effects, especially psychoactive side effects with Δ9-tetrahydrocannabinol treatment. This has led again to a search for methods to improve cannabinoid therapy. For this reason, research has focused on the ~150 terpene compounds found in Cannabis, which impart flavor and aroma to the plant. Limited evidence suggests that terpenes produce pain relief on their own, and they have also been proposed to modulate and potentially improve the effects of cannabinoids like THC, termed the “entourage effect” hypothesis. However the quality of evidence on terpene efficacy is in general poor, limited by poorly-defined and complex extracts, and few mechanistic studies. We thus performed a preliminary study on the Cannabis terpenes α- humulene, β-pinene, geraniol, and linalool. We found that all 4 terpenes produced anti-nociception in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) comparable or better than morphine. At the same time, geraniol and linalool produced no reward or aversion, suggesting no addictive or aversive liability. Seeking mechanistic insight, we found that all 4 terpenes produced tail flick anti- nociception by a cannabinoid receptor type 1 (CB1) mechanism, and further synergized with the cannabinoid WIN55,212, providing evidence for the entourage effect hypothesis. We further identified CB2, Adenosine A2a, and anti-inflammatory activity as potential mechanisms of action. In this proposal, we will extend these studies to evaluate therapeutic potential and mechanisms of action of these terpenes in neuropathic pain, providing potential support to the use of these ligands as improved non-opioid pain therapeutics. In Aim 1, we will fully test the terpenes in a mouse model of CIPN, including dose/response, alternate neuropathy models, side effects like tolerance and reward/aversion, synergy with other analgesics such as opioids and cannabinoids, and terpene impact on side effects of these other analgesics (especially opioid reward). In Aim 2, we will identify molecular mechanisms for terpene action in CIPN, focusing on 1) CB1/2, 2) A2a, and 3) anti-inflammatory activity. We will use selective antagonists and CRISPR gene editing, identify sites of action (e.g. brain, spinal cord, periphery), measure tissue response to terpene (e.g. cytokine production), and use in vitro models to confirm these mechanisms. Together these studies will provide a rigorous evaluation of the potential use of terpenes as efficacious and low side-effect therapeutics for neuropathic pain.

抽象的慢性疼痛在美国和世界范围内是一种严重且不断恶化的流行病，严重降低患者生活质量的阿片类药物（如吗啡）是治疗中度至中度的“金标准”。然而，严重的慢性疼痛却给他们带来了严重的副作用，尤其是成瘾倾向，这已经导致阿片类药物成瘾、滥用和过量的同时流行。此外，阿片类药物在治疗方面无效。一些疼痛类型，最明显的是神经性疼痛在寻找替代品时，来自大麻的植物大麻素。然而，大麻素通常被证明具有中等或较差的活性。功效，并有其自身的副作用，尤其是 Δ9-四氢大麻酚的精神副作用因此，这再次引发了寻找改善大麻素治疗方法的研究。重点研究大麻中发现的约 150 种萜烯化合物，这些化合物赋予植物风味和香气。有限的证据表明萜烯本身可以缓解疼痛，并且也有人建议它们调节并可能改善 THC 等大麻素的作用，称为“随行效应”假说。然而，由于定义不明确且复杂，萜烯功效的证据质量普遍较差。因此，我们对大麻萜烯 α- 进行了初步研究。葎草烯、β-蒎烯、香叶醇和芳樟醇我们发现所有 4 种萜烯都能产生抗伤害作用。化疗引起的周围神经病变（CIPN）小鼠模型与同时，香叶醇和芳樟醇没有产生奖赏或厌恶，表明没有成瘾性。寻求机制洞察，我们发现所有 4 种萜烯都会产生反甩尾作用。通过 1 型大麻素受体 (CB1) 机制产生伤害感受，并进一步与大麻素 WIN55,212，为随行效应假说提供了证据，我们进一步鉴定了 CB2，腺苷 A2a 和抗炎活性作为潜在的作用机制。扩展这些研究以评估这些萜烯在神经病中的治疗潜力和作用机制疼痛，为使用这些配体作为改进的非阿片类疼痛疗法提供潜在支持。我们将在 CIPN 小鼠模型中全面测试萜烯，包括剂量/反应、替代神经病模型、副作用，如耐受性和奖赏/厌恶，与其他镇痛药（如阿片类药物和大麻素）的协同作用，和萜烯对这些其他镇痛药（尤其是阿片类药物奖励）副作用的影响，我们将在目标 2 中确定。 CIPN 中萜烯作用的分子机制，重点关注 1) CB1/2、2) A2a 和 3) 抗炎我们将使用选择性拮抗剂和 CRISPR 基因编辑，识别作用位点（例如大脑、脊髓）。脊髓、外周），测量组织对萜的反应（例如细胞因子的产生），并使用体外模型来这些研究将共同证实这些机制，并对这些机制的潜在用途进行严格的评估。萜烯作为神经性疼痛的有效且低副作用的治疗剂。