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Targeting multiple enzyme systems to reduce arthritic pain and inflammation

针对多种酶系统来减轻关节炎疼痛和炎症

基本信息

批准号：
8878443
负责人：
Steven G. Kinsey
金额：
$ 39.51万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878443
关键词：
Absence of pain sensation Acute Pain Acute inflammatory pain Adverse effects Affect Analgesics Anti Inflammatory Analgesics Anti-Inflammatory Agents Anti-inflammatory Anxiety Arthritis Attenuated Brain Cannabinoids Cannabis Carrageenan Chronic Clinic Clinical Collagen-Induced Arthritis Cyclooxygenase Inhibitors Data Development Diclofenac Dose Drug Interactions Drug Modulation Endocannabinoids Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Esophageal FDA approved Genetic Goals Health Hemorrhage Human Hunger Hyperalgesia Individual Differences Inflammation Inflammation Mediators Inflammatory Inflammatory Arthritis Joints Lesion Life Long-Term Effects Mediator of activation protein Mental Depression Metabolic Modeling Motor Activity Mus Muscle Non-Steroidal Anti-Inflammatory Agents Outcome Pain Patients Pharmaceutical Preparations Physiological Pre-Clinical Model Property Prostaglandin-Endoperoxide Synthase Prostaglandins Reporting Research Rheumatoid Arthritis Sodium Spinal Cord Steroids Stomach Swelling Symptoms Synovial Fluid System Therapeutic Intervention Thermal Hyperalgesias Tissues Training Ulcer Work addiction anandamide arthritic pain attenuation base chemokine chronic pain cognitive function cytokine fatty acid amide hydrolase gastrointestinal graduate student in vivo inflammatory pain inhibitor/antagonist irritation joint injury liver function marijuana use mouse model next generation novel older patient public health relevance receptor research and development response undergraduate student

项目摘要

DESCRIPTION (provided by applicant): Extant drug treatments for pain, which is the most salient symptom of inflammatory arthritis, are limited by insufficient efficacy and negative side effects that range from gastrointestinal irritation to addiction. Cannabis has been used for millennia for its analgesic and anti-inflammatory properties. Although, the psychoactive effects and abuse potential have limited the broad use of cannabis, recent research has uncovered an endogenous cannabinoid (i.e., "endocannabinoid") receptor system that affects a broad range of health outcomes, including liver function, hunger, pain, anxiety, depression, and inflammation. The most studied endocannabinoid is anandamide (N- arachidonoylethanolamine), which is primarily metabolized in vivo by fatty acid amide hydrolase (FAAH). Pharmacological inhibition or genetic deletion of FAAH increases tissue levels of anandamide, reducing pain and inflammation, absent the psychomimetic side effects of Cannabis. In other words, FAAH inhibition reduced the pain response, but there are no observed changes in locomotor activity, muscle coordination, or cognitive function. We have recently reported that FAAH inhibition or genetic deletion of FAAH significantly attenuates pain and joint inflammation caused by the collagen-induced arthritis (CIA) model of inflammatory arthritis. We have also reported that FAAH inhibition augments the analgesic potency of the non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium in acute inflammatory pain. Co-administration of the FAAH inhibitor and NSAID is hypothesized to augment reductions in pain and inflammation in mice subjected to collagen-induced arthritis. We propose to determine if this drug interaction is additive or synergistic in attenuating pain (Aim 1) and joint inflammation (Aim 2). We also propose to determine which inflammatory factors (i.e., cytokines, chemokines, and prostaglandins) are critical in FAAH/NSAID modulation of joint inflammation, as reported in our preliminary data. We have also reported that FAAH inhibition blocks the development of gastric lesions caused by non-steroidal anti-inflammatory drugs. Thus, it may be possible not only to gain increased analgesic and anti-inflammatory efficacy by administering low doses of either drug, but also to avoid the side effects of high dose NSAIDs. In addition to having an important positive impact on patients, these data will inform research and development of next generation analgesic, anti-inflammatory treatments for inflammatory arthritis.

描述（由申请人提供）：现有的治疗疼痛的药物治疗是炎症性关节炎最显着的症状，但由于疗效不足和副作用（从胃肠道刺激到成瘾）而受到限制。大麻因其镇痛和抗炎特性而被使用了数千年。尽管大麻的精神作用和滥用潜力限制了大麻的广泛使用，但最近的研究发现，内源性大麻素（即“内源性大麻素”）受体系统会影响广泛的健康结果，包括肝功能、饥饿、疼痛、焦虑、抑郁和炎症。研究最多的内源性大麻素是 anandamide（N-花生四烯酰乙醇胺），它主要在体内通过脂肪酸酰胺水解酶（FAAH）代谢。 FAAH 的药理抑制或基因缺失会增加 anandamide 的组织水平，从而减轻疼痛和炎症，且不存在大麻的拟心理副作用。换句话说，FAAH 抑制减少了疼痛反应，但没有观察到运动活动、肌肉协调或认知功能的变化。我们最近报道，FAAH 抑制或 FAAH 基因缺失可显着减轻胶原诱导关节炎 (CIA) 炎症性关节炎模型引起的疼痛和关节炎症。我们还报道，FAAH 抑制增强了非甾体抗炎药 (NSAID) 双氯芬酸钠在急性炎症疼痛中的镇痛效力。据推测，FAAH 抑制剂和 NSAID 的共同给药可以增强胶原诱导关节炎小鼠的疼痛和炎症的减轻。我们建议确定这种药物相互作用在减轻疼痛（目标 1）和关节炎症（目标 2）方面是否具有相加或协同作用。正如我们初步数据中所报道的，我们还建议确定哪些炎症因子（即细胞因子、趋化因子和前列腺素）在 FAAH/NSAID 调节关节炎症中至关重要。我们还报道，FAAH 抑制可阻止非甾体抗炎药引起的胃病变的发展。因此，通过施用低剂量的任一药物不仅可以提高镇痛和抗炎功效，而且还可以避免高剂量非甾体抗炎药的副作用。除了对患者产生重要的积极影响外，这些数据还将为下一代炎症性关节炎镇痛、抗炎治疗的研究和开发提供信息。