MRGPRD is a G protein-coupled receptor primarily expressed in epidermal-innervating sensory neurons that mediates pain and itch sensations 1. The receptor couples to both Gq and Gi proteins, activating phospholipase C signaling and inhibiting adenylate cyclase, respectively 2. MRGPRD is activated by diverse ligands including β-alanine, β-aminoisobutyrate, and other endogenous metabolites 3. Functionally, MRGPRD+ neurons represent a major polymodal sensory population that mediates both mechanical pain and nonhistaminergic itch, with glutamate serving as a shared neurotransmitter for both modalities 1. In pain processing, MRGPRD is specifically required for mechanical hypersensitivity and cold allodynia in neuropathic pain models through a PKA-TRPA1 signaling pathway 4, while MRGPRD+ nociceptors drive reflexive protective responses to sustained pain stimuli 5. In itch signaling, the neuropeptide neuromedin B selectively complements MRGPRD-mediated glutamate release, enabling dedicated itch circuit processing 1. Beyond somatosensation, MRGPRD expression extends to intestinal smooth muscle, macrophages, and T lymphocytes, suggesting roles in immunity and intestinal function 6. Dysregulation of MRGPRD+ neuron excitability contributes to inflammatory itch and pain in conditions like contact hypersensitivity 7.