Endocannabinoid Modulation of Pruritus

描述(申请人提供)：瘙痒是临床术语，瘙痒，一种令人不快的轻微感觉，导致渴望抓挠受影响的区域。瘙痒会极大地降低患者的生活质量，进一步的后果可能包括基于抓挠的刺激和擦伤，通常还会导致失眠。由于瘙痒症状背后的病理生理条件的多样性(例如，过敏性、皮肤病和全身性)，常规治疗并不总是有效的。虽然没有关于寻求治疗瘙痒症的患病率的集体数据，但根据美国皮肤病学会的数据，仅皮肤病的数据就估计，任何时候都有三分之一的美国人患有瘙痒，每年的医疗费用为283亿美元。瘙痒与另一种新的感觉--疼痛--有许多共同的神经基础和信号特征。大麻素类化合物与THC(大麻中的主要活性成分)结合在同一受体上，通过外周、脊椎和大脑中大麻素受体的联合作用产生镇痛效应。在小型临床研究中，大麻素也显示出对瘙痒感觉的有效阻断，但大麻素在瘙痒症中的机制作用尚未得到很好的表征。随着内源性大麻素受体内源性配体的发现，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产生了越来越大的兴趣。这个项目的目标是使用瘙痒的行为小鼠模型来研究内源性大麻系统在抓挠反应中的变化。用肥大细胞脱颗粒剂化合物48/80或其他促瘙痒介质治疗小鼠，以诱导稳定的抓挠行为。这些方法将结合遗传模型(即转基因小鼠)和药理工具(如受体拮抗剂和酶抑制剂)来研究内源性大麻素在止痒中的受体机制、解剖位置和生理反应。最后，LC-MS定量测定关键解剖组织中的阿南达胺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，并阐明通过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.