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.
