title: Involvement of TRPV1 and TDAG8 in Pruriception Associated with Noxious Acidosis.
abstract: Itch and pain are closely related but are distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether acid (protons) can evoke itch like other algogens by spatial contrast activation of single nociceptors. Here, we report that (i) citric acid (0.2 mol/L) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin, (ii) acidified buffer elevated intracellular calcium levels in dorsal root ganglion pruriceptors, and (iii) 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, is 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+dorsal root ganglion pruriceptors. Itch induced by acidic citrate, but not α-methyl-5-hydroxytryptamine, chloroquine, compound 48/80, or bile acid, was markedly decreased in TDAG8-/-mice. In a heterologous expression system, TDAG8 potentiated the acid-induced calcium response by regulating TRPV1. Thus, protons could evoke pruriception by acting on TDAG8 to regulate TRPV1 activation with its mechanism of future therapeutic relevance.
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors: Shing-Hong
authors: SH
authors: Lin
authors: UCD Charles Institute of Dermatology, University College Dublin, Belfield, Dublin 4, Ireland; Department of Dermatology, University of California, San Diego, California, USA; Department of Dermatology, University of California, San Francisco, California, USA.
authors: Martin
authors: M
authors: Steinhoff
authors: Department of Dermatology, University of California, San Francisco, California, USA.
authors: Akihiko
authors: A
authors: Ikoma
authors: Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan.
authors: Yen-Ching
authors: YC
authors: Chang
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Department of Life Science, National Taiwan University, Taipei 106, Taiwan.
authors: Yuan-Ren
authors: YR
authors: Cheng
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University and Academia Sinica, Taipei 115, Taiwan.
authors: Ravi
authors: R
authors: Chandra Kopparaju
authors: Department of Immunology, Graduate School of Medicine, Akita University.
authors: Satoshi
authors: S
authors: Ishii
authors: Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan. Electronic address: weihsin@cc.ncu.edu.tw.
authors: Wei-Hsin
authors: WH
authors: Sun
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Department of Life Science, National Taiwan University, Taipei 106, Taiwan; Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang-Ming University and Academia Sinica, Taipei 115, Taiwan; Taiwan Mouse Clinic - National Comprehensive Phenotyping and Drug Testing Center, Academia Sinica, Taipei 115, Taiwan. Electronic address: chih@ibms.sinica.edu.tw.
authors: Chih-Cheng
authors: CC
authors: Chen
mesh_terms: D000138:Acidosis / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005561:Formates / Q000494:pharmacology*; D007271:Injections, Intradermal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000187:drug effects; D011537:Pruritus / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D005561:Formates; C513337:GPR65 protein, mouse; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C030544:formic acid