Inhibition of natriuretic peptide receptor 1 reduces itch in mice.

Let him that itches block NPR1: Chronic itch is an uncomfortable sensation with major impact on the quality of life. The pathophysiology of itch is not clearly elucidated, and the few available treatments are mostly ineffective. The natriuretic peptide receptor 1 (NPR1) has been recently shown to promote itch in mice; however, a peptide NPR1 inhibitor showed poor effects in mice. Investigating the reason for these negative results, Solinski et al. now show that the reported NPR1 inhibitor acted as partial agonist of the receptor, thus explaining the failure in relieving itch. Using high-throughput screening, the authors identified small-molecule human NPR1 antagonists. The molecules were able to relieve chronic itch in mice without inducing adverse effects. There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch– and chronic itch–challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch. [ABSTRACT FROM AUTHOR]