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

doi:10.1016/j.biopsych.2020.02.014

Biological Psychiatry

Volume 88, Issue 12, 15 December 2020, Pages 935-944

https://doi.org/10.1016/j.biopsych.2020.02.014 Get rights and content

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.

Section snippets

Subjects

We used male (n = 138) and female (n = 112) Sprague Dawley rats (Charles River Laboratories, Kingston, NY) weighing 250 to 350 g (males) or 175 to 225 g (females) before surgery. We maintained the rats under a reverse 12-hour light/dark cycle (8 am lights off) with food and water freely available. We housed 2 rats per cage before surgery and individually after surgery. We performed the experiments in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory

Oxycodone Self-administration (Context A)

In experiments 1 through 3, we trained the rats to self-administer oxycodone at 0.1 mg/kg/infusion for the first 7 days, followed by 0.05 mg/kg/infusion for the next 7 days. Rats of both sexes demonstrated reliable oxycodone self-administration as indicated by an increase in the number of oxycodone infusions and active lever presses over days and a compensatory increase in the number of infusions earned when we halved the dose (Figure 1, Figure 2, Figure 3; Table S1). There were no significant

Discussion

We combined a rat model of opioid maintenance (17, 18, 19) with a modified version of the ABA context-induced reinstatement model (20,21) to study prevention of relapse to oxycodone seeking and taking under chronic delivery of the G protein–biased MOR agonist TRV130. We report 4 main findings. First, the relapse model itself showed predictive validity when tested with the Food and Drug Administration–approved treatment buprenorphine (50). Second, the effects of buprenorphine in the model were

Acknowledgments and Disclosures

This work was supported by the National Institute on Drug Abuse Intramural Research Program funding to the Neurobiology of Relapse Section (principal investigator, YS).

JMB, EAK, HK, JKH, AA, DP, ST, and IF carried out the experiments. JMB, EAK, HK, JKH, and YS performed data analysis. JMB and YS designed the study and wrote the manuscript with SSN and DHE. BEB provided TRV130. SSN provided critical input on pharmacological aspects of the study. All authors critically reviewed the content and

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Archival ReportIn 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

Abstract

Background

Methods

Results

Conclusions

Section snippets

Subjects

Oxycodone Self-administration (Context A)

Discussion

Acknowledgments and Disclosures

J Subst Abuse Treat

J Sex Med

Clin Psychol Rev

Trends Pharmacol Sci

Prog Brain Res

Neuropharmacology

Life Sci

Neuropharmacology

Neurosci Biobehav Rev

Lancet

Neuropharmacology

Trends Pharmacol Sci

Pharmacol Biochem Behav

Neuropharmacology

Increases in drug and opioid overdose deaths—United States, 2000-2014

MMWR Morb Mortal Wkly Rep

Drug overdose deaths in the United States, 1999-2016

NCHS Data Brief

The opioid epidemic: Crisis and solutions

Annu Rev Pharmacol Toxicol

Overdose deaths involving opioids, cocaine, and psychostimulants—United States, 2015-2016

MMWR Morb Mortal Wkly Rep

A medical treatment for diacetylmorphine (heroin) addiction. A clinical trial with methadone hydrochloride

JAMA

Human pharmacology and abuse potential of the analgesic buprenorphine: A potential agent for treating narcotic addiction

Arch Gen Psychiatry

A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence

N Engl J Med

Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence

Cochrane Database Syst Rev

A call for evidence-based medical treatment of opioid dependence in the United States and Canada

Health Aff (Millwood)

Patterns of symptom complaints in methadone maintenance patients

Addiction

High prevalence of constipation and reduced quality of life in opioid-dependent patients treated with opioid substitution treatments

Expert Opin Pharmacother

Six deaths linked to concomitant use of buprenorphine and benzodiazepines

Addiction

Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning

Eur J Clin Pharmacol

Outpatient opiate detoxification treatment with buprenorphine. Preliminary investigation

Eur Addict Res

Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use

Neuropsychopharmacology

Relapse to heroin-seeking in rats under opioid maintenance: The effects of stress, heroin priming, and withdrawal

J Neurosci

Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement

Neuropsychopharmacology

Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking

Eur J Neurosci

Renewal of drug seeking by contextual cues after prolonged extinction in rats

Behav Neurosci

A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine

J Pharmacol Exp Ther

Bias factor and therapeutic window correlate to predict safer opioid analgesics

Cell

Archival Report
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