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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.

摘要