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Stemming the opioid-induced pain cascade via cannabinoid modulation

通过大麻素调节阻止阿片类药物引起的疼痛级联反应

基本信息

批准号：
10218325
负责人：
Steven G. Kinsey
金额：
$ 20.13万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218325
关键词：
2-arachidonylglycerol Acute Analgesics Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Attention Attenuated Behavior Behavioral Behavioral Model Binding Biological CNR1 gene CNR2 gene Cannabinoids Cannabis Chemicals Chronic Data Depressed mood Development Disease Drug Targeting Drug abuse Endocannabinoids Enzymes Experimental Animal Model Female Genetic Glycerol Goals Gold Harvest Human Hyperalgesia Immunologics In Vitro Incubated Individual Inflammation Inflammatory Injury Literature MAGL inhibitor Measures Modeling Monoacylglycerol Lipases Morphine Morphine Users Motivation Mus Needlestick Injuries Neurons Opiate Addiction Opioid Pain Painless Pathway interactions Perception Peripheral Pharmaceutical Preparations Pharmacology Physiological Physiological Processes Postoperative Pain Postoperative Period Property Quality of life Relapse Reporting Research Risk Spinal Cord Splenocyte Stimulus Substance Use Disorder Surface Surgical incisions Surgical sutures TLR4 gene Testing Therapeutic Therapeutic Intervention Thermal Hyperalgesias Tissues Translational Research Treatment outcome Withdrawal Woman allodynia base cannabinoid receptor cannabinoid receptor antagonist combat conditioning cytokine dependence relapse desensitization drug relapse effective therapy endogenous cannabinoid system exogenous cannabinoid inflammatory pain macrophage male marijuana use mechanical allodynia monocyte morphine administration mu opioid receptors neurobehavioral novel strategies opioid abuse opioid epidemic opioid exposure opioid sparing opioid use opioid use disorder opioid user opioid withdrawal pain perception pain sensitivity painful neuropathy preclinical study prescription opioid prevent receptor relating to nervous system response sex side effect stem substance abuse treatment

项目摘要

Despite their abuse potential, opioids remain a gold standard analgesic. One of the lesser discussed effects of chronic opioid use is opioid induced hyperalgesia (OIH), or increased pain sensitivity in some users. OIH persists for a longer duration than opioid withdrawal and may contribute to drug seeking and relapse in people with substance use disorders. The physiological causes of OIH are caused by (1) repeated µ opioid activation and desensitization, and (2) activation of inflammatory pathways by morphine binding to Toll-like receptor 4. Cannabinoids have well established analgesic and anti-inflammatory properties. Endogenous cannabinoids (i.e., endocannabinoids) have anti-inflammatory effects with limited intoxicating effects, as compared with exogenous cannabinoids. The proposed study will use an experimental animal model of repeated morphine exposure, followed by paw incision injury. Our goal is to test the hypothesis that inhibition of the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL) decreases pain and inflammation caused by repeated morphine treatment. Male and female mice will be repeatedly administered morphine or vehicle, in the presence of increased endocannabinoid tone, for four days. Endocannabinoid tone will be increased by either chemical inhibition of MAGL, or genetic deletion of MAGL globally or on neurons only. Then, a small incision will be made and sutured closed in the plantar surface of one hindpaw, to model postoperative hyperalgesia. Mice will be tested repeatedly for pain- induced, pain-suppressed, and pain conditioning behavioral models. Endocannabinoid receptor mechanism will be determined using selective CB1 and CB2 cannabinoid receptor antagonists. Paw tissue will be collected to quantify proinflammatory cytokine levels, and individual cytokine levels will be correlated with pain-related behaviors. The anti-inflammatory mechanisms of endocannabinoid modulation will be further probed in vitro, using isolated macrophages/monocytes. Extant studies of preclinical OIH models have used male animals almost exclusively. Because women may be at increased risk for developing OIH, we will include sufficient numbers of both female and male mice to investigate Sex as a Biological Variable. In addition to increasing basic understanding of the underlying neural and immunological mechanisms that contribute to opioid-induced hyperalgesia, our translational research goal is to develop treatments for substance abuse disorders.

尽管有滥用的可能，阿片类药物仍然是一种黄金标准的镇痛药。小众之一