{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:31:50Z","timestamp":1793723510289,"version":"4.6.1"},"reference-count":43,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T00:00:00Z","timestamp":1518134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001797","name":"Pharmaceutical Research and Manufacturers of America Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA R01 035316, DA RO1 023252"],"award-info":[{"award-number":["DA R01 035316, DA RO1 023252"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA 035316"],"award-info":[{"award-number":["DA 035316"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008455","name":"Medical School, University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008455","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>GPCRs exist in multiple conformations that can engage distinct signalling mechanisms which in turn may lead to diverse behavioural outputs. In rodent models, activation of the \u03b4 opioid receptor (\u03b4\u2010receptor) has been shown to elicit antihyperalgesia, antidepressant\u2010like effects and convulsions. We recently showed that these \u03b4\u2010receptor\u2010mediated behaviours are differentially regulated by the GTPase\u2010activating protein regulator of G protein signalling 4 (RGS4), which facilitates termination of G protein signalling. To further evaluate the signalling mechanisms underlying \u03b4\u2010receptor\u2010mediated antihyperalgesia, antidepressant\u2010like effects and convulsions, we observed how changes in G\u03b1<jats:sub>o<\/jats:sub>or arrestin proteins<jats:italic>in vivo<\/jats:italic>affected behaviours elicited by the \u03b4\u2010receptor agonist SNC80 in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Transgenic mice with altered expression of various signalling molecules were used in the current studies. Antihyperalgesia was measured in a nitroglycerin\u2010induced thermal hyperalgesia assay. Antidepressant\u2010like effects were evaluated in the forced swim test. Mice were also observed for convulsive activity following SNC80 treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In G\u03b1<jats:sub>o<\/jats:sub>RGS\u2010insensitive heterozygous knock\u2010in mice, the potency of SNC80 to produce antihyperalgesia and antidepressant\u2010like effects was enhanced with no change in SNC80\u2010induced convulsions. Conversely, in G\u03b1<jats:sub>o<\/jats:sub>heterozygous knockout mice, SNC80\u2010induced antihyperalgesia was abolished while antidepressant\u2010like effects and convulsions were unaltered. No changes in SNC80\u2010induced behaviours were observed in arrestin 3 knockout mice. SNC80\u2010induced convulsions were potentiated in arrestin 2 knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Taken together, these findings suggest that different signalling molecules may underlie the convulsive effects of the \u03b4\u2010receptor relative to its antihyperalgesic and antidepressant\u2010like effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14131","type":"journal-article","created":{"date-parts":[[2017,12,26]],"date-time":"2017-12-26T13:42:39Z","timestamp":1514295759000},"page":"891-901","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Role of signalling molecules in behaviours mediated by the \u03b4 opioid receptor agonist SNC80"],"prefix":"10.1111","volume":"175","author":[{"given":"Isaac J","family":"Dripps","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Michigan Medical School Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett T","family":"Boyer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Michigan Medical School Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R","family":"Neubig","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology Michigan State University East Lansing MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenner C","family":"Rice","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse North Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1849-8316","authenticated-orcid":false,"given":"John R","family":"Traynor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Michigan Medical School Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1154-1684","authenticated-orcid":false,"given":"Emily M","family":"Jutkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Michigan Medical School Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,2,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13884"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13878"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/7854_2012_224"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-2982.2009.01864.x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5449.2495"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.036525"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(01)00413-4"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.06.003"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.10.029"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/S0022-3565(25)39544-3","article-title":"Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice","volume":"267","author":"Comer SD","year":"1993","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_10_12_1","volume-title":"Guide for the care and use of laboratory animals","author":"Council NR","year":"2011"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12856"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708118200"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-016-4432-5"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.03.130"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3758\/BF03193146"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2007.06.005"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1124\/mol.108.054296","article-title":"Regulator of G protein signaling protein suppression of G\u03b1o protein\u2010mediated \u03b12A adrenergic receptor inhibition of mouse hippocampal CA3 epileptiform activity","volume":"75","author":"Goldstein BL","year":"2009","journal-title":"Mol Pharmacol"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3727\/107156998819565947","article-title":"Convulsive behavior of nonpeptide \u03b4\u2010opioid ligands: comparison of SNC80 and BW373U86 in mice","volume":"3","author":"Hong EJ","year":"1998","journal-title":"Analgesia"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.060251"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1159\/000186688"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.095810"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.91"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5470-12.2013"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm8008986"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12955"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.10.015"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2007.03.031"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M910348199"},{"key":"e_1_2_10_33_1","first-page":"327","article-title":"Behavioral despair in mice: a primary screening test for antidepressants","volume":"229","author":"Porsolt RD","year":"1977","journal-title":"Arch Int Pharmacodyn Ther"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02075.x"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-9-8"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12591"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4124-15.2016"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(72)90177-0"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.010909.105800"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2011.04.041"},{"key":"e_1_2_10_41_1","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/S0022-3565(24)37425-7","article-title":"Delta opioid receptor subtypes activate inositol\u2010signaling pathways in the production of antinociception","volume":"285","author":"S\u00e1nchez\u2010Bl\u00e1zquez P","year":"1998","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_10_42_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0026-895X(25)09224-7","article-title":"Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits","volume":"50","author":"Standifer KM","year":"1996","journal-title":"Mol Pharmacol"},{"key":"e_1_2_10_43_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1124\/mi.5.1.7","article-title":"Regulators of G protein signaling and drugs of abuse","volume":"5","author":"Traynor JR","year":"2005","journal-title":"Mol Intern"},{"key":"e_1_2_10_44_1","first-page":"249","article-title":"Expression of novel splice variants of the G protein subunit, Go\u03b1, is tissue\u2010specific and age\u2010dependent in the rat","volume":"296","author":"Yoo JH","year":"2002","journal-title":"Gnere"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.14131","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.14131","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T07:09:29Z","timestamp":1751180969000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.14131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,9]]},"references-count":43,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1111\/bph.14131"],"URL":"https:\/\/doi.org\/10.1111\/bph.14131","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,9]]},"assertion":[{"value":"2017-07-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-11-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-02-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}