{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:30:16Z","timestamp":1791469816193,"version":"4.3.4"},"reference-count":57,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2017,6,2]],"date-time":"2017-06-02T00:00:00Z","timestamp":1496361600000},"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","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["F32\u2010AR\u2010062927"],"award-info":[{"award-number":["F32\u2010AR\u2010062927"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K01\u2010AR\u2010070328"],"award-info":[{"award-number":["K01\u2010AR\u2010070328"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010064251"],"award-info":[{"award-number":["R01\u2010AR\u2010064251"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010060364"],"award-info":[{"award-number":["R01\u2010AR\u2010060364"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To determine the ability of drugs that activate inhibitory G protein\u2013coupled receptors (GPCRs) expressed in peripheral voltage\u2010gated sodium channel 1.8 (Na<jats:sub>V<\/jats:sub>1.8)\u2013positive sensory neurons to control osteoarthritis (OA)\u2013associated pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used designer receptors exclusively activated by a designer drug (DREADD) technology, which employs engineered GPCRs to activate or inhibit neurons upon binding the synthetic ligand clozapine <jats:italic>N<\/jats:italic>\u2010oxide (CNO). Na<jats:sub>V<\/jats:sub>1.8\u2010Pdi C57BL\/6 mice were generated to express the inhibitory DREADD receptor Pdi in Na<jats:sub>V<\/jats:sub>1.8\u2010expressing sensory neurons. Destabilization of the medial meniscus (DMM) surgery was performed in 10\u2010week\u2010old male mice. Four, 8, 12, or 16 weeks after surgery, knee hyperalgesia or hind paw mechanical allodynia was tested. Subsequently, CNO or vehicle was administered, and the effect on pain\u2010related behaviors was measured by a blinded observer. Morphine was used as a control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Immunohistochemistry and electrophysiology confirmed functional expression of the inhibitory DREADD receptor Pdi by Na<jats:sub>V<\/jats:sub>1.8\u2010positive sensory neurons. Acute inhibition of Na<jats:sub>V<\/jats:sub>1.8\u2010expressing neurons in mice treated with CNO reduced knee hyperalgesia 4 weeks after DMM surgery and reduced mechanical allodynia 8 weeks after DMM surgery. Inhibition had no effect on pain\u2010related behaviors 12 and 16 weeks after DMM surgery. Morphine, a drug that activates GPCRs in the peripheral and central nervous systems, was still effective in the later stage of experimental OA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Chemogenetic inhibition of Na<jats:sub>V<\/jats:sub>1.8\u2010expressing neurons blocks knee hyperalgesia and mechanical allodynia in early experimental OA, but is no longer efficacious in the later stages. These data indicate that activation of inhibitory GPCRs located solely outside the central nervous system may be ineffective in treating chronic OA pain.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40118","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T18:34:49Z","timestamp":1491417289000},"page":"1429-1439","source":"Crossref","is-referenced-by-count":64,"title":["Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis"],"prefix":"10.1002","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4486-5757","authenticated-orcid":false,"given":"Rachel E.","family":"Miller","sequence":"first","affiliation":[{"name":"Rush University Medical Center Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Ishihara","sequence":"additional","affiliation":[{"name":"Rush University Medical Center Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bula","family":"Bhattacharyya","sequence":"additional","affiliation":[{"name":"Northwestern University Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"Delaney","sequence":"additional","affiliation":[{"name":"Rush University Medical Center Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela M.","family":"Menichella","sequence":"additional","affiliation":[{"name":"Northwestern University Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Miller","sequence":"additional","affiliation":[{"name":"Northwestern University Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Marie","family":"Malfait","sequence":"additional","affiliation":[{"name":"Rush University Medical Center Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,6,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21596"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2014.01.003"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30002-2"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R115.654764"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318238bba6"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2008.12.017"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-014-0717-9"},{"key":"e_1_2_6_9_1","first-page":"CD003115","article-title":"Oral or transdermal opioids for osteoarthritis of the knee or hip","author":"Da Costa BR","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.2174\/157015906778019527"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2008.01671.x"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074706"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.36076\/ppj.2011\/14\/249"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2007.12.017"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2013.03.018"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2007.03.006"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38876"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1209294110"},{"key":"e_1_2_6_19_1","unstructured":"GlassonSS HopkinsB AttipoeS SchellingS MorrisEA.ADAMTS\u20105 KO mice are protected in a long\u2010term instability model of osteoarthritis [poster]. Presented at the 53rd Annual Meeting of the Orthopaedic Research Society;2007; San Diego California."},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37900"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054633"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2015.09.005"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.46"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2009.11.013"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2015.12.014"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39291"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2008.05.012"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2011.09.007"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2007.02.012"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1358\/mf.2010.32.8.1532102"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23870"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2014.03.016"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700293104"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010814-124803"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1205295"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2012.04.022"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3553"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.03.042"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.08.015"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2010.05.025"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2012.02.009"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.034"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.019"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1063-4584(03)00163-8"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.08.004"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1532-2149.2012.00176.x"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2006.05.001"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2006.12.022"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003145"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2008.12.009"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0444-16.2016"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0140-15.2016"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.138"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(88)90027-9"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.02.008"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(92)90262-A"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3978"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2016.04.016"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.40118","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.40118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T14:04:12Z","timestamp":1759932252000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.40118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,2]]},"references-count":57,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2017,7]]}},"alternative-id":["10.1002\/art.40118"],"URL":"https:\/\/doi.org\/10.1002\/art.40118","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,2]]}}}