Submitted by Hristelina Ilieva, MD, PhD
Edited by Elliot Bodofsky, MD
Inhibition of Natriuretic Peptide Receptor 1 Reduces Itch in Mice
. Hans Jürgen Solinski1, Patricia Dranchak2, Erin Oliphant2, Xinglong Gu1, Thomas W. Earnest1, John Braisted2, James Inglese2 and Mark A. Hoon. Science Translational Medicine
10 Jul 2019: Vol. 11, Issue 500, eaav5464, DOI: 10.1126/scitranslmed.aav5464.
This study uses in vitro and in vivo experimental models to clarify the physiology of itch. Using high-throughput screening human natriuretic peptide receptor one (hNPR1) antagonists were identified, one of which can relieve itch in vivo in mouse models.
Itch stimuli are thought to be detected in the skin by dedicated sensory neurons that express G-protein coupled, Toll-like, and interleukin receptors. Known receptors are many, but the number of cell types that detect it are small and involves two populations – mas-related G protein- coupled receptor A3 (Mrgpra3) and those expressing the neuropeptide natriuretic polypeptide b (NPPB). Both of these classes of neurons transmit itch through a common spinal cord circuit dependent on NPPB. Additionally, sensory neuron-derived NPPB is thought to drive inflammation in different forms of dermatitis, enhancing pruritus. This, together with elevated NPPD levels in renal failure, leads to the choice of NPPB as a target for investigation. NPPB is expressed in a subset of human DRG neurons and is co-expressed with the two receptors hNPR1 and MRGPRX1. High throughput screening identified 15 new hNPR1 antagonists, and these are likely to act as noncompetitive inhibitors of NPR1. One of the compounds readily crossed the blood brain barrier and reached concentrations that predict mouse NPR1 inhibition. Unwanted side effects of NPR1 inhibition were described. NPR1 is expressed in kidney and vasculature. Cardiovascular effects were not present. The authors indicate that future systematic side effects studies are needed.
Having more specific therapeutic targets than anti-histamine medications, which cause sedation, is a welcome future development. The paper allows a better understanding of the neurophysiology of itch. NM specialists see a variety of neuropathies, particularly uremic neuropathy patients, with very frequent complaints of itching. Being aware of the neurophysiology and that future therapeutic targets exist will be helpful.