Critical Role of R7 Binding Protein in the Sensation of Acute and Pathologic Itch

Abstract

Itch is a common irritating sensation, which triggers a desire to scratch. Itch sensation could be triggered due to potentially harmful agents such as insects, parasites and certain plant alkaloids or in a variety of diseases conditions such as eczema, dry skin itch or jaundice or peripheral neuropathies.In the present study we identified R7BP, a palmitoylated membrane anchoring protein that facilitates Gαi/o –mediated GTPase activating protein (GAP) activity, diminishes scratching in response to a number of pruritogens administerd either intradermally in the nape of the neck or in the central nervous system by lumbar puncture. However, when tested to a number of sensory nociceptive modalities which included mechanical, heat and chemically induced pain, the R7BP KO mice did not show any significant changes except in response to the heat induced pain. The pruriceptive defect in R7bp KO was reversed in a double knock out mice also lacking OPRK1, encoding the Gαi/o coupled kappa opioid receptor.A similar pruriceptive phenotype was observed in a knock‐in of GAP‐insensitive mutant mice with a Gαo (Gnao1 G184s/+) mutation. Further in a model of atopic dermatitis, R7BP KO mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists as compared to wild type littermates.Based on our observations, R7BP has an important role to play in somatosensory itch sensation and probably it functions by modulating the kappa opioid receptor. Our findings also suggest that Gαo has a significant role in itch perception and it could be involved regulation of kappa opioid receptor activity to modulate itch sensation.Taken together, our results indicate that R7BP is a key regulator of itch sensation and suggest that the potential targeting of R7BP – dependent GAP activity as a novel therapeutic strategy for pathologic itch.Support or Funding InformationThis research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Dental and Craniofacial Research