Targeting multiple enzyme systems to reduce arthritic pain and inflammation

 描述（由申请人提供）：疼痛是炎性关节炎最显著的症状，现有的疼痛药物治疗受到疗效不足和不良副作用（从胃肠道刺激到成瘾）的限制。大麻因其止痛和抗炎特性而被使用了数千年。虽然，精神活性作用和滥用潜力限制了大麻的广泛使用，但最近的研究发现了一种内源性大麻素（即，内源性大麻素（“endocannabinoid”）受体系统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大麻素（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的药理学抑制或基因缺失增加了大麻素的组织水平，减少了疼痛和炎症，没有大麻的拟精神副作用。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。我们最近报道了FAAH抑制或FAAH基因缺失显著减轻由炎性关节炎的胶原诱导的关节炎（CIA）模型引起的疼痛和关节炎症。我们还报道了FAAH抑制增强了非甾体抗炎药（NSAID）双氯芬酸钠在急性炎性疼痛中的镇痛效力。假设FAAH抑制剂和NSAID的共同施用增加了经受胶原诱导的关节炎的小鼠中疼痛和炎症的减少。我们建议确定这种药物相互作用在减轻疼痛（目的1）和关节炎症（目的2）方面是相加的还是协同的。我们还建议确定哪些炎症因子（即，细胞因子、趋化因子和类胡萝卜素）在FAAH/NSAID调节关节炎症中是关键的。我们还报道了FAAH抑制阻断非甾体抗炎药引起的胃病变的发展。因此，不仅可以通过给予低剂量的任一种药物来获得增加的镇痛和抗炎功效，而且可以避免高剂量NSAID的副作用。除了对患者产生重要的积极影响外，这些数据还将为炎症性关节炎的下一代镇痛抗炎治疗的研究和开发提供信息。

 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.