Cross-Talk between Distinct Receptors Shapes Itch Behavior in the Spinal Cord

Natriuretic peptide (NP) family comprises multiple peptides/receptors whose respective role in itch transmission remains unclear. We report that about 23% of Npr1 that encodes NP receptor A (NPRA) in the superficial spinal cord co-express gastrin-releasing peptide (Grp), while Npr3 that encodes NP receptor C (NPRC), partially overlaps with the neuromedin B receptor (NMBR) required for histamine-evoked itch. While Npr1 is required for chloroquine- (CQ) and histamine-evoked itch, the role of Npr3 is limited to the latter. Notably, B-type natriuretic peptide (BNP) significantly facilitated NMB-, but not GRP-, evoked scratching behavior, and Ca2 response in NMBR/NPRC cells. Consistently, BNP-saporin ablated spinal Npr1 and Npr3 neurons and impaired histamine-, but not CQ-evoked, itch. Thus, the findings identify the role of BNP-NPRC signaling in modulation of histamine-evoked itch via NPRC-NMBR cross-talk independent of GRP-GRPR signaling. Our studies reveal distinct modes of action for bombesin-related peptides and NP in itch transmission.