Jennifer M Bossert1, Eugene A Kiyatkin2, Hannah Korah2, Jennifer K Hoots2, Anum Afzal2, David Perekopskiy2, Shruthi Thomas2, Ida Fredriksson2, Bruce E Blough3, S Stevens Negus4, David H Epstein5, Yavin Shaham2. 1. Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland. Electronic address: jennifer.bossert@nih.gov. 2. Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland. 3. Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina. 4. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia. 5. Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.
Abstract
BACKGROUND: Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model. METHODS: We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels. RESULTS: In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone. CONCLUSIONS: TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction. Published by Elsevier Inc.
BACKGROUND: Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model. METHODS: We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels. RESULTS: In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone. CONCLUSIONS: TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction. Published by Elsevier Inc.
Entities:
Keywords:
Buprenorphine; Context; Drug cues; Drug self-administration; Extinction; G protein–biased MOR agonists; Oxycodone; Reacquisition; Reinstatement; Relapse; Sex differences; TRV130
Authors: Fabio Lugoboni; Antonio Mirijello; Lorenzo Zamboni; Marco Faccini; Rebecca Casari; Anthony Cossari; Antonio Gasbarrini; Giovanni Addolorato Journal: Expert Opin Pharmacother Date: 2016-09-21 Impact factor: 3.889
Authors: Barbara R Haight; Susan M Learned; Celine M Laffont; Paul J Fudala; Yue Zhao; Amanda S Garofalo; Mark K Greenwald; Vijay R Nadipelli; Walter Ling; Christian Heidbreder Journal: Lancet Date: 2019-02-18 Impact factor: 79.321
Authors: Milan D Valyear; Mandy R LeCocq; Alexa Brown; Franz R Villaruel; Diana Segal; Nadia Chaudhri Journal: Psychopharmacology (Berl) Date: 2022-10-20 Impact factor: 4.415
Authors: E Andrew Townsend; Kathryn L Schwienteck; Hannah L Robinson; Stephen T Lawson; Matthew L Banks Journal: J Neurosci Methods Date: 2021-03-08 Impact factor: 2.390
Authors: Eden M Anderson; Annabel Engelhardt; Skyler Demis; Elissa Porath; Matthew C Hearing Journal: Neuropsychopharmacology Date: 2021-05-19 Impact factor: 8.294
Authors: Brianna E George; Samuel H Barth; Lindsey B Kuiper; Katherine M Holleran; Ryan T Lacy; Kimberly F Raab-Graham; Sara R Jones Journal: Neuropsychopharmacology Date: 2021-05-26 Impact factor: 8.294
Authors: Caroline B Pantazis; Luis A Gonzalez; Brendan J Tunstall; Stephanie A Carmack; George F Koob; Leandro F Vendruscolo Journal: Sci Adv Date: 2021-04-07 Impact factor: 14.136