Spinal BNP-NPRA Signaling in Regulating Itch and Pain in Primates

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

Itch/Pruritus is a symptom derived from many nervous system disorders that afflicts a large population worldwide and is treated by a variety of pharmacological agents with variable success. Little effort has been made to develop valid nonhuman primate models of itch for preclinical evaluation of potential antipruritics. Given that monkeys and humans have similar thresholds for detecting sensory stimuli and monkey models provide the most phylogenetically appropriate evaluation of receptor functions and drug effects, pharmacological studies in monkeys may establish a translational bridge for the therapeutic profiles of drugs in humans. This application will integrate behavioral pharmacology with immunohistochemistry to establish the functional profile of a ligand-receptor system (i.e., B- type natriuretic peptide (BNP)-Natriuretic peptide receptor-A (NPRA)) for regulating itch and pain in the spinal cord of monkeys. Using pharmacological approaches, we intend to establish centrally-elicited itch models using BNP, gastrin-releasing peptide (GRP) and ?- endorphin, and to evaluate the effectiveness of the NPRA antagonist as an antipruritic in a broader context in conscious, behaving monkeys implanted with the intrathecal catheter. The proposed studies in this project will mainly validate whether BNP has a selective functional role for regulating itch and/or pain and will assess the potential treatment efficacy of the NPRA antagonist in these primate models. In addition, the protein levels of BNP and GRP and their cognate receptors will be examined in the dorsal root ganglion and spinal cord of monkeys. Collectively, this novel and translational research project will examine for the first time the localization and anatomical site of action of BNP and GRP and their cognate receptors in regulating itch in primates. These studies will not only improve scientific knowledge of neuropeptides such as BNP, but also advance the discovery of innovative therapies targeting the BNP-NPRA versus GRP-GRP receptor signaling for the treatment of pruritus in humans.