Endocannabinoid Modulation of Pruritus

描述（由申请人提供）：瘙痒是瘙痒的临床术语，是一种令人不快的伤害性感觉，导致想要抓挠受影响区域。瘙痒症可大大降低患者的生活质量，瘙痒症的进一步后果可包括基于抓挠的刺激和擦伤，以及常见的失眠。由于病理生理条件的多样性（例如，过敏性的、皮肤病学的和全身性的）潜在的瘙痒症，常规的治疗并不总是有效的。虽然没有关于寻求瘙痒症治疗的流行率的集体数据，但根据美国皮肤病学会的数据，仅皮肤病的发病率就估计在任何特定时刻都有三分之一的美国人受到折磨，每年花费283亿美元用于医疗。瘙痒与另一种伤害性感觉疼痛的神经基质和信号特征有很多共同之处。大麻素与THC（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联合作用产生镇痛作用。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。来自细胞膜内磷脂的大麻素受体的内源性配体的发现（例如，大麻素（anandamide）和2-AG）已经引起了对内源性大麻素系统和控制内源性大麻素张力的酶调节剂的越来越多的兴趣。本研究的目的是利用瘙痒症的行为小鼠模型，通过内源性大麻素系统研究抓挠反应的改变。小鼠用肥大细胞去甲肾上腺素化合物48/80或其它促炎介质处理，以诱导稳定水平的抓挠行为。方法将联合收割机遗传模型（即转基因小鼠）和药理学工具（例如，受体拮抗剂和酶抑制剂）来研究内源性大麻素在瘙痒管理中的受体机制、解剖学位点和生理反应。最后，LC-MS定量的大麻素，和其他脂肪酸酰胺的水平，在关键的解剖组织将允许检查的生理反应的内源性大麻素系统的条件下的反式压力。这些研究将进一步了解内源性大麻素系统的生理功能，以及阐明通过内源性大麻素系统介导的瘙痒症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.