{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T14:05:27Z","timestamp":1778767527822,"version":"3.51.4"},"reference-count":42,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R42DA056254"],"award-info":[{"award-number":["R42DA056254"]}],"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":["R37DA039997"],"award-info":[{"award-number":["R37DA039997"]}],"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":["T32DA007281"],"award-info":[{"award-number":["T32DA007281"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["T32TR004764"],"award-info":[{"award-number":["T32TR004764"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM008597"],"award-info":[{"award-number":["T32 GM008597"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM007767"],"award-info":[{"award-number":["T32 GM007767"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jpet.aspetjournals.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"published-print":{"date-parts":[[2026,4]]},"DOI":"10.1016\/j.jpet.2026.104304","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:11:28Z","timestamp":1771459888000},"page":"104304","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["A mu-opioid receptor positive allosteric modulator provides opioid-sparing antinociception without enhancing opioid side effects"],"prefix":"10.1016","volume":"393","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6340-3822","authenticated-orcid":false,"given":"Kelsey E.","family":"Kochan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8032-0298","authenticated-orcid":false,"given":"Benjamin M.","family":"Clements","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2363-366X","authenticated-orcid":false,"given":"Thomas D.","family":"Prince","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2349-3613","authenticated-orcid":false,"given":"Catherine","family":"Demery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D.","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica S.","family":"Levitt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1849-8316","authenticated-orcid":false,"given":"John R.","family":"Traynor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/joacp.JOACP_362_19","article-title":"Opioid sparing strategies for perioperative pain management other than regional anaesthesia: a narrative review","volume":"38","author":"Ghai","year":"2022","journal-title":"J Anaesthesiol Clin Pharmacol"},{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib3","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.urology.2011.09.037","article-title":"The effect of noise-cancelling headphones or music on pain perception and anxiety in men undergoing transrectal prostate biopsy","volume":"79","author":"Tsivian","year":"2012","journal-title":"Urology"},{"issue":"10004","key":"10.1016\/j.jpet.2026.104304_bib4","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/S0140-6736(15)60169-6","article-title":"Music as an aid for postoperative recovery in adults: a systematic review and meta-analysis","volume":"386","author":"Hole","year":"2015","journal-title":"Lancet"},{"issue":"3","key":"10.1016\/j.jpet.2026.104304_bib5","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1136\/acupmed-2013-010498","article-title":"Effect of perioperative electroacupuncture as an adjunctive therapy on postoperative analgesia with tramadol and ketamine in prostatectomy: a randomised sham-controlled single-blind trial","volume":"32","author":"Ntritsou","year":"2014","journal-title":"Acupunct Med"},{"issue":"6","key":"10.1016\/j.jpet.2026.104304_bib6","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1213\/ANE.0b013e31828f2d5e","article-title":"Acupuncture is theatrical placebo","volume":"116","author":"Colquhoun","year":"2013","journal-title":"Anesth Analg"},{"key":"10.1016\/j.jpet.2026.104304_bib7","series-title":"Pain Management in Special Circumstances","article-title":"Non-pharmacological pain management","author":"El Geziry","year":"2018"},{"key":"10.1016\/j.jpet.2026.104304_bib8","article-title":"Non-pharmacological pain management practice and associated factors among nurses working at comprehensive specialized hospitals","volume":"9","author":"Tsegaye","year":"2023","journal-title":"SAGE Open Nurs"},{"issue":"6","key":"10.1016\/j.jpet.2026.104304_bib9","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1097\/ACO.0000000000000396","article-title":"An update on pain management for elderly patients undergoing ambulatory surgery","volume":"29","author":"Cao","year":"2016","journal-title":"Curr Opin Anaesthesiol"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib10","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1213\/ANE.0b013e3182334d68","article-title":"Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials","volume":"114","author":"De Oliveira","year":"2012","journal-title":"Anesth Analg"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib11","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1213\/ANE.0b013e31823cd524","article-title":"Ketorolac: its role as part of a multimodal analgesic regimen","volume":"114","author":"White","year":"2012","journal-title":"Anesth Analg"},{"issue":"12","key":"10.1016\/j.jpet.2026.104304_bib12","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1016\/j.clinthera.2019.10.002","article-title":"Perioperative opioid-sparing strategies: utility of conventional NSAIDs in adults","volume":"41","author":"Martinez","year":"2019","journal-title":"Clin Ther"},{"issue":"10","key":"10.1016\/j.jpet.2026.104304_bib13","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s12630-011-9560-0","article-title":"A systematic review of intravenous ketamine for postoperative analgesia","volume":"58","author":"Laskowski","year":"2011","journal-title":"Can J Anaesth"},{"issue":"6","key":"10.1016\/j.jpet.2026.104304_bib14","doi-asserted-by":"crossref","first-page":"524","DOI":"10.4097\/kjae.2013.64.6.524","article-title":"Opioid sparing effect of low dose ketamine in patients with intravenous patient-controlled analgesia using fentanyl after lumbar spinal fusion surgery","volume":"64","author":"Kim","year":"2013","journal-title":"Korean J Anesthesiol"},{"issue":"5","key":"10.1016\/j.jpet.2026.104304_bib15","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1213\/ANE.0000000000002497","article-title":"A review of opioid-sparing modalities in perioperative pain management: methods to decrease opioid use postoperatively","volume":"125","author":"Kumar","year":"2017","journal-title":"Anesth Analg"},{"issue":"2S1","key":"10.1016\/j.jpet.2026.104304_bib16","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1097\/TA.0000000000003695","article-title":"Opioid sparing effect of ketamine in military prehospital pain management-a retrospective study","volume":"93","author":"Cohen","year":"2022","journal-title":"J Trauma Acute Care Surg"},{"issue":"7","key":"10.1016\/j.jpet.2026.104304_bib17","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/s41386-022-01322-4","article-title":"Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies","volume":"47","author":"Nielsen","year":"2022","journal-title":"Neuropsychopharmacology"},{"issue":"11","key":"10.1016\/j.jpet.2026.104304_bib18","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1016\/j.jpain.2022.06.009","article-title":"Real-time monitoring of cannabis and prescription opioid co-use patterns, analgesic effectiveness, and the opioid-sparing effect of cannabis in individuals with chronic pain","volume":"23","author":"Mun","year":"2022","journal-title":"J Pain"},{"key":"10.1016\/j.jpet.2026.104304_bib19","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2020-047717","article-title":"Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies","volume":"11","author":"Noori","year":"2021","journal-title":"BMJ Open"},{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib20","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1038\/s41467-024-47792-6","article-title":"Structural and dynamic insights into the activation of the \u03bc-opioid receptor by an allosteric modulator","volume":"15","author":"Kaneko","year":"2024","journal-title":"Nat Commun"},{"issue":"26","key":"10.1016\/j.jpet.2026.104304_bib21","doi-asserted-by":"crossref","first-page":"10830","DOI":"10.1073\/pnas.1300393110","article-title":"Discovery of positive allosteric modulators and silent allosteric modulators of the \u03bc-opioid receptor","volume":"110","author":"Burford","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.jpet.2026.104304_bib22","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.32499","article-title":"Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor","volume":"7","author":"Livingston","year":"2018","journal-title":"Elife"},{"issue":"16","key":"10.1016\/j.jpet.2026.104304_bib23","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2000017118","article-title":"Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects","volume":"118","author":"Kandasamy","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"51","key":"10.1016\/j.jpet.2026.104304_bib24","doi-asserted-by":"crossref","first-page":"18369","DOI":"10.1073\/pnas.1415013111","article-title":"Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor","volume":"111","author":"Livingston","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1021\/acschemneuro.4c00541","article-title":"Structure-activity relationships and molecular pharmacology of positive allosteric modulators of the mu-opioid receptor","volume":"16","author":"Li","year":"2025","journal-title":"ACS Chem Neurosci"},{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib26","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J Neurosci Methods"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib27","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1124\/mol.117.109561","article-title":"Pharmacologic evidence for a putative conserved allosteric site on opioid receptors","volume":"93","author":"Livingston","year":"2018","journal-title":"Mol Pharmacol"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib28","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.pbb.2004.12.002","article-title":"A preclinical comparison between different opioids: antinociceptive versus adverse effects","volume":"80","author":"Meert","year":"2005","journal-title":"Pharmacol Biochem Behav"},{"key":"10.1016\/j.jpet.2026.104304_bib29","series-title":"Opioids in Pain Control: Basic and Clinical Aspects","first-page":"46","article-title":"Supraspinal mechanisms in opioid analgesia","author":"Heinricher","year":"1998"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1601-183X.2005.00143.x","article-title":"Mouse strain differences in autonomic responses to stress","volume":"5","author":"van Bogaert","year":"2006","journal-title":"Genes Brain Behav"},{"issue":"9","key":"10.1016\/j.jpet.2026.104304_bib31","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/npp.2017.66","article-title":"Strained in planning your mouse background? Using the HPA stress axis as a biological readout for backcrossing strategies","volume":"42","author":"Chan","year":"2017","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib32","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.pbb.2011.07.013","article-title":"Regional mRNA expression of the endogenous opioid and dopaminergic systems in brains of C57BL\/6J and 129P3\/J mice: strain and heroin effects","volume":"100","author":"Schlussman","year":"2011","journal-title":"Pharmacol Biochem Behav"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3344\/kjp.2019.32.2.69","article-title":"Opioid-induced constipation: a narrative review of therapeutic options in clinical management","volume":"32","author":"Lang-Illievich","year":"2019","journal-title":"Korean J Pain"},{"issue":"Suppl 1","key":"10.1016\/j.jpet.2026.104304_bib34","first-page":"S39","article-title":"Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans","volume":"6 Spec No","author":"Demetrius","year":"2005","journal-title":"EMBO Rep"},{"issue":"6","key":"10.1016\/j.jpet.2026.104304_bib35","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1097\/00000542-199412000-00008","article-title":"Fentanyl, esmolol, and clonidine blunt the transient cardiovascular stimulation induced by desflurane in humans","volume":"81","author":"Weiskopf","year":"1994","journal-title":"Anesthesiology"},{"issue":"3","key":"10.1016\/j.jpet.2026.104304_bib36","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1213\/00000539-197905000-00004","article-title":"Cardiovascular effects of fentanyl during enflurane anesthesia in man","volume":"58","author":"Bennett","year":"1979","journal-title":"Anesth Analg"},{"issue":"7","key":"10.1016\/j.jpet.2026.104304_bib37","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1111\/bph.15580","article-title":"Understanding and countering opioid-induced respiratory depression","volume":"180","author":"Bateman","year":"2023","journal-title":"Br J Pharmacol"},{"issue":"1","key":"10.1016\/j.jpet.2026.104304_bib38","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1113\/JP278612","article-title":"Differential impact of two critical respiratory centres in opioid-induced respiratory depression in awake mice","volume":"598","author":"Varga","year":"2020","journal-title":"J Physiol"},{"key":"10.1016\/j.jpet.2026.104304_bib39","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.52694","article-title":"Opioids depress breathing through two small brainstem sites","volume":"9","author":"Bachmutsky","year":"2020","journal-title":"Elife"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib40","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/bph.14860","article-title":"Fentanyl depression of respiration: comparison with heroin and morphine","volume":"177","author":"Hill","year":"2020","journal-title":"Br J Pharmacol"},{"issue":"3","key":"10.1016\/j.jpet.2026.104304_bib41","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1007\/BF00432213","article-title":"Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning","volume":"86","author":"Mucha","year":"1985","journal-title":"Psychopharmacology (Berl)"},{"issue":"2","key":"10.1016\/j.jpet.2026.104304_bib42","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1097\/FBP.0b013e32835f3d2f","article-title":"Inhibition of G\u03b2\u03b3-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward","volume":"24","author":"Hoot","year":"2013","journal-title":"Behav Pharmacol"},{"issue":"4","key":"10.1016\/j.jpet.2026.104304_bib43","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nrd3673","article-title":"Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain","volume":"11","author":"Roques","year":"2012","journal-title":"Nat Rev Drug Discov"}],"container-title":["The Journal of Pharmacology and Experimental Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356526005033?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022356526005033?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:14:10Z","timestamp":1777450450000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022356526005033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["S0022356526005033"],"URL":"https:\/\/doi.org\/10.1016\/j.jpet.2026.104304","relation":{},"ISSN":["0022-3565"],"issn-type":[{"value":"0022-3565","type":"print"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"A mu-opioid receptor positive allosteric modulator provides opioid-sparing antinociception without enhancing opioid side effects","name":"articletitle","label":"Article Title"},{"value":"The Journal of Pharmacology and Experimental Therapeutics","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jpet.2026.104304","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics.","name":"copyright","label":"Copyright"}],"article-number":"104304"}}