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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

Published:February 24, 2020DOI:https://doi.org/10.1016/j.biopsych.2020.02.014

      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.

      Key words

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      Linked Article

      • Novel Application for G Protein–Biased Mu Opioid Receptor Agonists in Opioid Relapse Prevention
        Biological PsychiatryVol. 88Issue 12
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          For centuries, the most effective treatment for pain has been opioids, such as morphine, codeine and hydrocodone, which bind to mu opioid receptors (MORs) in the brain and spinal cord to produce their pain-relieving effects. Unfortunately, there are several side effects of long-term treatment with opioids, including respiratory depression, constipation, dependence, tolerance, and addiction, which limit their use. Historically, clinicians prescribed these pain treatments cautiously because of these adverse side effects.
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