Endocannabinoid Modulation of Pruritus

描述（由申请人提供）：瘙痒症是瘙痒的临床术语，是一种令人不快的讨厌的感觉，导致想要抓患处。瘙痒症会大大降低患者的生活质量，瘙痒症的进一步后果包括瘙痒性刺激和磨损，通常还会导致失眠。由于各种各样的病理生理条件（例如，过敏，皮肤和全身）瘙痒症状，常见的治疗方法并不总是有效的。虽然没有关于瘙痒症治疗的普遍程度的集体数据，但根据美国皮肤病学会的数据，在任何特定时刻，仅皮肤病的发病率就估计有三分之一的美国人患有瘙痒症，每年花费283亿美元用于医疗治疗。瘙痒的神经基质和信号特征与另一种有害的感觉疼痛有很多相同之处。大麻素与四氢大麻酚（大麻的主要活性成分）结合相同的受体，通过外周、脊柱和大脑中大麻素受体的共同作用产生镇痛作用。在小型临床研究中，大麻素也显示出对瘙痒感知的有效阻断，但大麻素在瘙痒中的机制作用尚未得到很好的表征。内源性大麻素受体配体的发现来源于细胞膜内的磷脂（例如，anandamide和2-AG），这引起了人们对内源性大麻素系统和控制内源性大麻素张力的酶调节因子的兴趣日益增加。这个项目的目的是调查在抓挠反应的变化，内源性大麻素系统，使用行为小鼠模型的瘙痒。用肥大细胞脱颗粒化合物48/80或其他致痒介质治疗小鼠，以诱导稳定水平的抓挠行为。方法将结合遗传模型（如转基因小鼠）和药理学工具（如受体拮抗剂和酶抑制剂）来研究内源性大麻素在治疗瘙痒中的受体机制、解剖位点和生理反应。最后，在关键解剖组织中，LC-MS定量anandamide和其他脂肪酸酰胺的水平将允许检查内源性大麻素系统在瘙痒应激条件下的生理反应。这些研究将进一步了解内源性大麻素系统的生理功能，并阐明内源性大麻素系统介导的瘙痒的潜在靶点和治疗方法。

DESCRIPTION (provided by applicant): Pruritus is the clinical term for itch, an unpleasant nocifensive sensation that results in the desire to scratch the affected area. Pruritus can greatly reduce the quality of life of those inflicted, and further consequences of pruritus can include scratching-based irritations and abrasion, and commonly insomnia. Due to the variety of pathophysiological conditions (e.g., allergenic, dermatologic, and systemic) underlying pruritus symptomology, common treatments are not always effective. While there are no collective data on the prevalence of treatment seeking for pruritus, the numbers on skin diseases alone estimates an incidence of 1 in 3 Americans afflicted at any given moment, and costing a yearly $28.3 billion in medical treatment according to the American Academy of Dermatology. Pruritus shares much of its neural substrates and signaling characteristics with that of another nocifensive sensation, pain. Cannabinoids, which bind to the same receptors as THC (the primary active component in marijuana), produce analgesic effects mediated through combined action of cannabinoid receptors in the periphery, spine, and brain. Cannabinoids have also shown effective blockade of itch perception in small clinical studies, but the mechanistic actions of Cannabinoids in pruritus are not well characterized. The discovery of endogenous ligands for the cannabinoid receptors derived from phospholipids within cellular membranes (e.g., anandamide and 2-AG) has generated increasing interest in the endocannabinoid system, and the enzymatic regulators that control endocannabinoid tone. The goal of this project is investigating the alterations in scratching response, by the endocannabinoid system, using a behavioral mouse model of pruritus. Mice are treated with the mast cell degranulator compound 48/80, or other pruritogenic mediators, to induce stable levels of scratching behavior. Approaches will combine both genetic models (i.e. transgenic mice) and pharmacological tools (e.g., receptor antagonists and enzyme inhibitors) to investigate the receptor mechanisms, anatomical loci, and physiologic response of endocannabinoids in management of itch. Finally, LC-MS quantification of anandamide, and levels of other fatty acid amides, in key anatomical tissues will allow examination of the physiologic response of the endocannabinoid system under conditions of pruritic stress. These studies will further the understanding of the physiological functions of the endocannabinoid system, as well as elucidate potential targets and treatments of pruritus mediated through the endocannabinoid system.