{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T12:09:11Z","timestamp":1776859751049,"version":"3.51.2"},"reference-count":43,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,3,19]],"date-time":"2017-03-19T00:00:00Z","timestamp":1489881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS054791"],"award-info":[{"award-number":["R01NS054791"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Chloroquine (CQ) stimulates itch nerves and causes intense scratching in mice by activating the G\u2010protein coupled receptor (GPCR) MrgprA3; it is not known how stimulation of MrgprA3 (or other GPCRs) leads to activation of the itch nerve terminals in the skin, but previous studies have found that transient receptor potential A1 (TRPA1) gene deletion blocks CQ\u2010induced scratching.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the present study we used a novel dorsal skin\u2013nerve preparation to evaluate mechanisms underlying CQ\u2010 and histamine\u2010induced action potential discharge in itch nerve terminals.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We found that CQ activation of the nerves requires the beta3 isoform of phospholipase C, but TRPA1 or other TRP channel are not required.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Evidence is provided for a role for calcium\u2010activated chloride channels such as TMEM16a in GPCR\u2010activation of itch nerve terminals.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The mechanism by which TRP channels participate in pruritogen\u2010induced scratching may involve sites of action other than the primary afferent terminals.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Chloroquine (CQ) and histamine are pruritogens commonly used to study itch in the mouse. A novel skin\u2013nerve preparation was used to evaluate chloroquine (CQ)\u2010 and histamine\u2010induced activation of afferent nerves in the dorsal thoracic skin of the mouse. All CQ sensitive nerves were C\u2010fibres, and were also sensitive to histamine. The response to CQ, but not histamine, was largely absent in mrgpr\u2010cluster \u0394<jats:sup>\u2212\/\u2212<\/jats:sup> mice, supporting the hypothesis that CQ evokes itch largely via stimulation of MrgprA3 receptors. The CQ\u2010induced action potential discharge was largely absent in phospholipase C\u03b23 knockout animals. The CQ and histamine responses were not influenced by removal of TRPA1, TRPV1, TRPC3 or TRPC6, nor by the TRP channel blocker Ruthenium Red. The bouts of scratching in response to CQ were not different between wild\u2010type and TRPA1\u2010deficient mice. A selective inhibitor of the calcium\u2010activated chloride channel TMEM16A, <jats:italic>N<\/jats:italic>\u2010((4\u2010methoxy)\u20102\u2010naphthyl)\u20105\u2010nitroanthranilic acid (MONNA), inhibited CQ\u2010induced action potential discharge at itch nerve terminals and bouts of scratching by about 50%. Although TRPA1 and TRPV1 channels may be involved in the scratching responses to intradermal pruritogens, this is unlikely to be due to an effect at the nerve terminals, where chloride channels may play a more important role.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp273795","type":"journal-article","created":{"date-parts":[[2017,2,20]],"date-time":"2017-02-20T04:22:48Z","timestamp":1487564568000},"page":"3651-3666","source":"Crossref","is-referenced-by-count":66,"title":["Mechanisms of pruritogen\u2010induced activation of itch nerves in isolated mouse skin"],"prefix":"10.1113","volume":"595","author":[{"given":"F.","family":"Ru","sequence":"first","affiliation":[{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2210-4930","authenticated-orcid":false,"given":"D.","family":"Jurcakova","sequence":"additional","affiliation":[{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore MD USA"},{"name":"Department of Pathophysiology, Biomedical Centre Martin, Jessenius Medical School Comenius University  Martin Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2303-0144","authenticated-orcid":false,"given":"R. A.","family":"Herbstsomer","sequence":"additional","affiliation":[{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Meixong","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X.","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-9029","authenticated-orcid":false,"given":"B. J.","family":"Undem","sequence":"additional","affiliation":[{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,3,19]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2014.03.026"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.07.035"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1201\/b16573-20"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3619"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13201"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12786"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00465a022"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1600990"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.09.085"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3289"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192565799"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.148304"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905605106"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.054890"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3641"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2251"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.087577"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.08.042"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2297-08.2008"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-229948"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41084"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.11.034"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-012-1202-1"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.066381"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300300"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.113.087502"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.02.006"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.237115"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1201\/b16573-10"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3404"},{"key":"e_1_2_6_33_1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1523\/JNEUROSCI.16-01-00082.1996","article-title":"Regulation of intracellular Cl\u2212 levels by Na+\u2010dependent Cl\u2212 cotransport distinguishes depolarizing from hyperpolarizing GABAA receptor\u2010mediated responses in spinal neurons","volume":"16","author":"Rohrbough J","year":"1996","journal-title":"J\u00a0Neurosci"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1308963111"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-015-1687-3"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.450072"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3881"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009555"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623309357953"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1201\/b16573-17"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2789"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5318-12.2013"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1208814"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1732949100"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP273795","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP273795","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T19:27:53Z","timestamp":1696188473000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP273795"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,19]]},"references-count":43,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1113\/JP273795"],"URL":"https:\/\/doi.org\/10.1113\/jp273795","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,19]]}}}