Ph.D. University College London, UK
Itch and pain are closely related but distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether proton can evoke itch like other algogens at the basis of spatial contrast activation of single nociceptors. Here, we report that (1) citric acid (0.2 M) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin; (2) acidified buffer elevated intracellular calcium levels in dorsal root ganglion (DRG) pruriceptors; (3) injection of intradermal citric acid (pH 3.0) into the nape induced a pruritogen-like but not algogen-like c-Fos immunoreactivity pattern in the cervical spinal cord. Using pharmacological and genetic approaches, we identified potential acid-sensing channels/receptors involved in acidic citrate-evoked itch. Results indicate that TRPV1 but neither ASIC3 nor TRPA1 are involved in the acidic citrate-induced scratching response. Furthermore, one of the proton-sensing G-protein-coupled receptors, TDAG8, was highly (∼71%) expressed in Nppb+ DRG pruriceptors. Acidic citrate but not α-methyl-5-HT, chloroquine, compound 48/80 or bile acid-induced itch was markedly decreased in TDAG8-/- mice. In a heterologous expression system, TDAG8 potentiated the acid-induced calcium response by regulating TRPV1. Thus, proton could evoke pruriception by acting on TDAG8 to regulate TRPV1 activation with its mechanism of future therapeutic relevance.