In a Rat Model of Opioid Maintenance, the G Protein-Biased Mu Opioid Receptor Agonist TRV130 Decreases Relapse to Oxycodone Seeking and Taking and Prevents Oxycodone-Induced Brain Hypoxia

Biol Psychiatry. 2020 Dec 15;88(12):935-944. doi: 10.1016/j.biopsych.2020.02.014. Epub 2020 Feb 24.


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.

Keywords: Buprenorphine; Context; Drug cues; Drug self-administration; Extinction; G protein–biased MOR agonists; Oxycodone; Reacquisition; Reinstatement; Relapse; Sex differences; TRV130.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Analgesics, Opioid
  • Animals
  • Extinction, Psychological
  • Female
  • GTP-Binding Proteins
  • Humans
  • Hypoxia, Brain*
  • Male
  • Oxycodone*
  • Rats
  • Receptors, Opioid, mu / metabolism
  • Recurrence
  • Self Administration
  • Spiro Compounds
  • Thiophenes


  • ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine
  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • Spiro Compounds
  • Thiophenes
  • Oxycodone
  • GTP-Binding Proteins