Endogenous Cannabinoids and NGF Signaling in Pain Associated with Cystitis

描述(由申请人提供)：痛性膀胱疾病的特征是尿频、尿急和衰弱的骨盆疼痛，在美国有超过150万人受到影响。据估计，慢性盆腔疼痛患者的年治疗成本高达30亿美元。内脏痛是最令人衰弱的症状，内脏痛背后的神经机制在很大程度上仍不清楚。目前可用的控制膀胱疼痛的选择并不是对所有患者都有效。内源性大麻素(内源性大麻素)具有限制炎性疼痛的功能，但对其在膀胱中的作用知之甚少。我们已经发现，膀胱炎刺激内源性大麻素的释放，尤其是花青胺(AEA)。以往的研究表明，炎症组织释放的炎性介质，特别是神经生长因子(NGF)，在传入神经敏化和内脏痛的发生中起着重要作用。这项研究将采用独特的方法来测量炎症反应下膀胱释放的内源性大麻素，以及抑制脂肪酸酰胺水解酶(FAAH)对膀胱疼痛的影响。FAAH是AEA代谢的主要酶。我们将利用包括膜片钳研究在内的体外技术，进一步研究大麻类化合物抑制NGF对传入背根节神经元敏化的能力。我们还将使用FAAH或主要大麻素受体之一(CB1或CB2)缺陷的小鼠来测试新的假设，即内源性大麻素可以抑制由膀胱炎引起的内脏疼痛，并且这种作用至少部分是通过抑制NGF的作用来介导的。长期目标是为膀胱疼痛的治疗或预防提供改进的选择，与目前可用的治疗选择相比，这些选择具有更少的不良副作用。

DESCRIPTION (provided by applicant): Painful bladder disorders are characterized by urinary frequency, urgency, and debilitating pelvic pain that affect more than 1.5 million people in the United States. Estimates of the annualized cost of treatment of patients with chronic pelvic pain range up to $3 billion. Visceral pain is the most debilitating symptom, and neurological mechanisms underlying visceral pain remain largely unknown. Currently available options for controlling bladder pain are not effective in all patients. Endogenous cannabinoids (endocannabinoids) function to limit inflammatory pain, but very little is known about their function in the bladder. We have found that inflammation of the bladder stimulates release of endocannabinoids, particularly anandamide (AEA). Previous research indicates that inflammatory mediators, particularly nerve growth factor (NGF), released from inflamed tissues play an important role in sensitization of afferent nerves and development of visceral pain. This research will employ unique methodology to measure release of endocannabinoids by the bladder in response to inflammation and the effects of inhibition of fatty acid amide hydrolase (FAAH, the enzyme primarily responsible for metabolism of AEA) on bladder pain. We will further investigate the capacity of cannabinoids to inhibit sensitization of afferent dorsal root ganglia neurons by NGF using in vitro techniques, including patch clamp studies. We will also use mice that are deficient in FAAH or one of the primary cannabinoid receptors (CB1 or CB2) to test the novel hypothesis that endocannabinoids inhibit visceral pain arising from bladder inflammation and that this effect is mediated at least in part by inhibition of the effects of NGF. The long range goal is to provide improved options for treatment or prevention of bladder pain that have fewer undesirable side effects than those associate with currently-available therapeutic options.