title: Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine.
abstract: The sensations of pain, itch, and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1(+), TRPV1(+), and TRPM8(+) neurons and thus affects the sensations of pain, itch, and cold. Here, we show that only 43% of CQ-excited dorsal root ganglion neurons expressed TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or TRPV1 antagonist but was prevented by the general transient receptor potential canonical (TRPC) channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1(+) neurons and concomitant inhibition of TRPM8 in 48.8% of TRPM8(+) dorsal root ganglion neurons. Sensitization of TRPV1 is caused mainly by activation of the phospholipase C-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Gαq independent of the phospholipase C pathway. Our data suggest the involvement of the TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly exciting itch-encoding neurons but also exerts previously unappreciated widespread actions on pain-, itch-, and cold-sensing neurons, leading to enhanced pain and itch.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.
authors.forename: Jonathan Y-X L
authors.initials: JY
authors.lastname: Than
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Raquibul
authors.initials: R
authors.lastname: Hasan
authors.forename: Xuming
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000563:Amebicides / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012677:Sensation / Q000187:drug effects / Q000502:physiology; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000083:Acetanilides; D000563:Amebicides; D000813:Anilides; D011687:Purines; D011720:Pyrazoles; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C492297:TRPM8 protein, mouse; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; D013830:Thiadiazoles; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate; D002738:Chloroquine; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: Calcium Imaging; Chloroquine; Electrophysiology; G Protein-coupled Receptor (GPCR); Itch; Pain; Sensory Transduction; Signal Transduction; TRP Channels