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We hypothesized that an analogue of CJ\u201015,208, <jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe], would demonstrate multifunctional \u03bc\u2010opioid receptor and \u03ba\u2010opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective \u03bc\u2010opioid receptor agonists, while preventing both drug\u2010 and stress\u2010induced reinstatement of morphine\u2010induced CPP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The opioid receptor agonist and antagonist activity of <jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe] was characterized after i.c.v. and i.p. administration to C57BL\/6J or transgenic opioid receptor \u201cknockout\u201d mice using the 55\u00b0C warm\u2010water tail\u2010withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of <jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe] to block morphine\u2010 and stress\u2010induced reinstatement of extinguished CPP was determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p><jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe] demonstrated dose\u2010dependent, short\u2010lasting antinociception, with an ED<jats:sub>50<\/jats:sub> (and 95% confidence interval) of 0.15 (0.05\u20130.21) nmol i.c.v. and 1.91 (0.40\u20133.54) mg\u00b7kg<jats:sup>\u22121<\/jats:sup> i.p., mediated by \u03bc\u2010 and \u03ba\u2010opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose\u2010dependent \u03ba\u2010opioid receptor antagonist\u2010like activity at 2.5, but not at 4.5, h after administration. <jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at \u03ba\u2010receptors. Pretreatment with <jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe] prevented stress\u2010 and drug\u2010induced reinstatement of extinguished morphine\u2010place preference responses in a time\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These data suggest that <jats:italic>cyclo<\/jats:italic>[Pro\u2010Sar\u2010Phe\u2010<jats:sc>d<\/jats:sc>\u2010Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug\u2010 and stress\u2010induced relapse in morphine\u2010abstinent subjects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15165","type":"journal-article","created":{"date-parts":[[2020,6,20]],"date-time":"2020-06-20T01:00:01Z","timestamp":1592614801000},"page":"4209-4222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Multifunctional opioid receptor agonism and antagonism by a novel macrocyclic tetrapeptide prevents reinstatement of morphine\u2010seeking behaviour"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6107-2743","authenticated-orcid":false,"given":"Ariana C.","family":"Brice\u2010Tutt","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa L.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shainnel O.","family":"Eans","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather M.","family":"Stacy","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chloe A.","family":"Simons","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grant G.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy S.","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-3126","authenticated-orcid":false,"given":"Michael J.","family":"Ferracane","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7954-9850","authenticated-orcid":false,"given":"Jane V.","family":"Aldrich","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9851-9342","authenticated-orcid":false,"given":"Jay P.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, College of Pharmacy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,7,16]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9105-4"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910180106"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/np300697k"},{"key":"e_1_2_12_5_1","first-page":"S104","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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