Regulation of Itch Scratching by Spinal GRP Receptors in Primates

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DESCRIPTION (provided by applicant): Pruritus (itch sensation) is a symptom derived from many nervous system disorders that afflicts a large population of humans and is treated by a variety of pharmacological agents with variable success. Little effort has been made to develop valid animal models of itch for preclinical evaluation of potential antipruritics. Recent studies illustrate distinct species differences in the in vivo pharmacology of itch, which may contribute t different results or interpretations in itch research. Humans and monkeys have similar thresholds for detecting stimuli and the neural systems responsible for sensations in both species are fundamentally similar. Therefore, it is important to conduct studies using conscious behaving monkeys to validate animal behavioral models and to assess the effectiveness of potential antipruritics. In particular, previous studies have demonstrated that intrathecally administered morphine-induced scratching behavior in monkeys is mediated by central mu opioid receptors. Using pharmacological approaches, we intend to establish other experimental itch models using endogenous pruritogenic agents including ¿-endorphin and gastrin-releasing peptide and to evaluate the effectiveness of gastrin-releasing peptide receptor (GRPR) antagonists as antipruritics in a broader context in behaving monkeys. The proposed studies in this project will mainly develop and validate the monkey models of itch elicited by intrathecal administration of various ligands and will assess the potential treatment efficacy of GRPR antagonists in these models. In the proposed studies, scratching activity will be monitored by video recorders and quantified by observers blind to experimental conditions. The potential attenuation of scratching activity by rationally selected pharmacological agents will be studied in different experimental itch models. The dose- response curve, time course of each agent, and possible side effects will be thoroughly investigated. Collectively, these studies will develop vald animal models of itch, improve scientific knowledge of GRPR in primates, and advance the discovery of innovative therapies targeting the GRPR for the treatment of pruritus in humans.