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：
10271680
负责人：
John Michael Streicher
金额：
$ 32.08万
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/10271680
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 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 animal pain 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.

抽象的慢性疼痛是美国和全球的严重且令人担忧的流行病降解患者生活质量。如吗啡（例如吗啡）等阿片类药物是将中度治疗的“黄金标准” 然而，严重的慢性疼痛被重大副作用所燃烧，尤其是成瘾责任，这有促成了阿片类药物成瘾，滥用和过量的流行病。另外，阿片类药物无效一些疼痛类型，最著名的是神经性疼痛。在寻找替代方案时，大麻的植物大麻素 Sativa一直在研究。但是，大麻素通常已被证明是适度的效应，并具有自己的副作用，尤其是与Δ9-四氢大麻酚的精神活性副作用治疗。这再次导致寻找改善大麻素治疗的方法。因此，研究专注于大麻中发现的约150种萜烯化合物，这些化合物赋予了植物的风味和香气。有限的证据表明，萜烯会自行减轻疼痛，并且还提议他们调节并有可能改善THC等大麻素的作用，称为“随行效应”假设。但是，关于萜烯效率的证据质量通常是较差的，受到定义较差且复杂的限制提取物，很少的机械研究。因此，我们对大麻萜烯α-进行了初步研究 Humulene，β-pineene，Geraniol和Linalool。我们发现所有4种萜烯均在A中产生抗伤害感受。化学疗法诱导的外周神经病（CIPN）的小鼠模型可比或更好吗啡。同时，Geraniol和Linalool不会产生任何奖励或厌恶，建议没有添加剂或厌恶责任。寻求机械洞察力，我们发现所有4种萜烯均产生尾巴抗大麻素受体1型（CB1）机制的伤害感受，并进一步与大麻素Win55,212，提供了启用效应假设的证据。我们进一步确定了CB2，腺苷A2a和抗炎活性作为作用的潜在机制。在此提案中，我们将扩展这些研究以评估这些萜烯在神经疗法中的治疗潜力和作用机制疼痛，为这些配体的使用提供潜在的支持，以改善非阿片类药物疼痛疗法。在AIM 1中，我们将在CIPN的小鼠模型中充分测试萜烯，包括剂量/反应，替代神经病模型，副作用，例如耐受性和奖励/厌恶，与其他镇痛药（例如阿片类药物和大麻素）协同作用，萜烯对这些其他镇痛药的副作用（尤其是阿片类药物奖励）的影响。在AIM 2中，我们将确定 CIPN中萜烯作用的分子机制，重点是1）CB1/2、2）A2A和3）抗炎活动。我们将使用选择性拮抗剂和CRISPR基因编辑，识别作用部位（例如大脑，脊柱绳索，外围），测量组织对萜烯的反应（例如细胞因子的产生），并使用体外模型确认这些机制。这些研究将共同对潜在使用的严格评估萜烯作为神经性疼痛的有效且低副作用疗法。