Endogenous Cannabinoids and NGF Signaling in Pain Associated with Cystitis

描述（由申请人提供）：疼痛性膀胱疾病的特征是尿频、尿急和使人虚弱的骨盆疼痛，在美国影响超过150万人。据估计，慢性盆腔疼痛患者的年治疗费用高达30亿美元。内脏疼痛是最使人衰弱的症状，内脏疼痛的神经机制在很大程度上仍然未知。目前可用的控制膀胱疼痛的方法并不是对所有患者都有效。内源性大麻素（endocannabinoids）的功能是限制炎症性疼痛，但很少有人知道他们在膀胱的功能。我们已经发现，膀胱炎症刺激内源性大麻素的释放，特别是大麻素（AEA）。以往的研究表明，炎症介质，特别是神经生长因子（NGF），从发炎的组织中释放的传入神经的敏感性和内脏痛的发展中发挥重要作用。这项研究将采用独特的方法来测量膀胱对炎症反应的内源性大麻素释放，以及抑制脂肪酸酰胺水解酶（FAAH，主要负责AEA代谢的酶）对膀胱疼痛的影响。我们将进一步研究大麻素的能力，抑制神经生长因子的传入背根神经节神经元的敏化使用体外技术，包括膜片钳研究。我们还将使用缺乏FAAH或主要大麻素受体之一（CB 1或CB 2）的小鼠来测试新的假设，即内源性大麻素抑制膀胱炎症引起的内脏疼痛，并且这种作用至少部分是通过抑制NGF的作用来介导的。长期目标是提供用于治疗或预防膀胱疼痛的改进的选择，其具有比与当前可用的治疗选择相关的那些更少的不良副作用。 公共卫生相关性：疼痛性膀胱疾病的特征在于尿频、尿急和使人虚弱的骨盆疼痛，在美国影响超过150万人，每年花费高达30亿美元。拟议的研究将调查通过操纵身体产生的内源性大麻素来控制膀胱疼痛的潜力，以通过抑制神经生长因子（NGF）（一种已知的膀胱疼痛介质）的作用来抑制疼痛。

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. PUBLIC HEALTH RELEVANCE: Painful bladder disorders are characterized by urinary frequency, urgency, and debilitating pelvic pain that affects more than 1.5 million people in the United States at an annual cost of as much as $3 billion. The proposed research will investigate the potential for control of bladder pain by manipulation of endogenous cannabinoids produced by the body to inhibit pain by suppressing the effects of nerve growth factor (NGF), a known mediator of bladder pain.