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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References
- Increases in drug and opioid overdose deaths—United States, 2000-2014.MMWR Morb Mortal Wkly Rep. 2016; 64: 1378-1382
- Drug overdose deaths in the United States, 1999-2016.NCHS Data Brief. 2017; 294: 1-8
- The opioid epidemic: Crisis and solutions.Annu Rev Pharmacol Toxicol. 2018; 58: 143-159
- Overdose deaths involving opioids, cocaine, and psychostimulants—United States, 2015-2016.MMWR Morb Mortal Wkly Rep. 2018; 67: 349-358
- A medical treatment for diacetylmorphine (heroin) addiction. A clinical trial with methadone hydrochloride.JAMA. 1965; 193: 646-650
- Human pharmacology and abuse potential of the analgesic buprenorphine: A potential agent for treating narcotic addiction.Arch Gen Psychiatry. 1978; 35: 501-516
- A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence.N Engl J Med. 2000; 343: 1290-1297
- Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.Cochrane Database Syst Rev. 2002; 4: CD002207
- A call for evidence-based medical treatment of opioid dependence in the United States and Canada.Health Aff (Millwood). 2013; 32: 1462-1469
- Symptom complaints of patients prescribed either oral methadone or injectable heroin.J Subst Abuse Treat. 2010; 38: 328-337
- Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment.J Sex Med. 2008; 5: 684-692
- Patterns of symptom complaints in methadone maintenance patients.Addiction. 1997; 92: 1445-1455
- High prevalence of constipation and reduced quality of life in opioid-dependent patients treated with opioid substitution treatments.Expert Opin Pharmacother. 2016; 17: 2135-2141
- Six deaths linked to concomitant use of buprenorphine and benzodiazepines.Addiction. 1998; 93: 1385-1392
- Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning.Eur J Clin Pharmacol. 2012; 68: 301-309
- Outpatient opiate detoxification treatment with buprenorphine. Preliminary investigation.Eur Addict Res. 1998; 4: 198-202
- Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use.Neuropsychopharmacology. 2004; 29: 1312-1320
- Relapse to heroin-seeking in rats under opioid maintenance: The effects of stress, heroin priming, and withdrawal.J Neurosci. 1996; 16: 1957-1963
- Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement.Neuropsychopharmacology. 2005; 30: 1681-1692
- Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking.Eur J Neurosci. 2019; 50: 2075-2085
- Renewal of drug seeking by contextual cues after prolonged extinction in rats.Behav Neurosci. 2002; 116: 169-173
- 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. 2013; 344: 708-717
- Sources of relapse after extinction in Pavlovian and instrumental learning.Clin Psychol Rev. 1991; 11: 123-140
- Biased ligands at G-protein-coupled receptors: Promise and progress.Trends Pharmacol Sci. 2014; 35: 308-316
- Bias factor and therapeutic window correlate to predict safer opioid analgesics.Cell. 2017; 171: 1165-1175.e1113
- Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents.J Psychopharmacol. 2017; 31: 730-739
- Phosphorylation-deficient G-protein-biased mu-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects.Nat Commun. 2019; 10: 367
- The novel mu-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.Br J Pharmacol. 2018; 175: 2653-2661
- A randomized, Phase IIb study investigating oliceridine (TRV130), a novel micro-receptor G-protein pathway selective (mu-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty.J Pain Res. 2017; 10: 2413-2424
- APOLLO-1: A randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the micro-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy.J Pain Res. 2019; 12: 927-943
- A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain.Pain. 2016; 157: 264-272
- APOLLO-2: A randomized, placebo and active-controlled phase iii study investigating oliceridine (TRV130), a G protein-biased ligand at the mu-opioid receptor, for management of moderate to severe acute pain following abdominoplasty.Pain Pract. 2019; 19: 715-731
- Animal models of drug relapse and craving: From drug priming-induced reinstatement to incubation of craving after voluntary abstinence.Prog Brain Res. 2016; 224: 25-52
- Relapse to opioid seeking in rat models: Behavior, pharmacology and circuits.Neuropsychopharmacology. 2019; 44: 465-477
- Predictive validity of the extinction/reinstatement model of drug craving.Psychopharamacology. 1998; 135: 151-160
- Extinction of drug seeking: Neural circuits and approaches to augmentation.Neuropharmacology. 2014; 76: 528-532
- Needle fixation, the drug user’s perspective: A qualitative study.Addiction. 2001; 96: 1049-1058
- Applying extinction research and theory to cue-exposure addiction treatments.Addiction. 2002; 97: 155-167
- Priming effects with drugs and other reinforcers.Exp Clin Psychopharmacol. 1996; 4: 5-10
- Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists.Life Sci. 1987; 40: 1287-1292
- Buprenorphine: A unique drug with complex pharmacology.Curr Neuropharmacol. 2004; 2: 395-402
- Changes in brain oxygen and glucose induced by oxycodone: Relationships with brain temperature and peripheral vascular tone.Neuropharmacology. 2018; 133: 481-490
- Opiate versus psychostimulant addiction: The differences do matter.Nat Rev Neurosci. 2011; 12: 685-700
- The reinstatement model of drug relapse: Recent neurobiological findings, emerging research topics, and translational research.Psychopharmacology. 2013; 229: 453-476
- Neural systems underlying opiate addiction.J Neurosci. 2002; 22: 3321-3325
- Opiate reward: sites and substrates.Neurosci Biobehav Rev. 1989; 13: 129-133
- Opioids, reward and addiction: An encounter of biology, psychology, and medicine.Pharmacol Rev. 1999; 51: 341-396
- Opioid receptors: Drivers to addiction?.Nat Rev Neurosci. 2018; 19: 499-514
- Neurobiology of opioid dependence in creating addiction vulnerability.F1000Res. 2016; 5
- Opioid drugs in maintenance and detoxification treatment of opiate addiction; addition of buprenorphine and buprenorphine combination to list of approved opioid treatment medications.Fed Regist. 2003; 68: 27937-27939
- The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration.Psychopharmacology. 2006; 188: 28-41
- Drug addiction and drug abuse.in: Gilman A.G. Rall T.W. Nies A.S. Taylor P. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. Pergamon Press, New York1990: 522-573
- Tolerance and dependence after continuous morphine infusion from osmotic pumps measured by operant responding in rats.Psychopharmacology. 1990; 100: 451-458
- Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation.Psychopharmacology. 1991; 103: 129-135
- The animal pharmacology of buprenorphine, an oripavine analgesic agent.Br J Pharmacol. 1977; 60: 547-554
- The effects of buprenorphine on self-administration of cocaine and heroin “speedball” combinations and heroin alone by rhesus monkeys.J Pharmacol Exp Ther. 1998; 285: 444-456
- Choice between heroin and food in nondependent and heroin-dependent rhesus monkeys: Effects of naloxone, buprenorphine, and methadone.J Pharmacol Exp Ther. 2006; 317: 711-723
- First clinical experience with TRV130: Pharmacokinetics and pharmacodynamics in healthy volunteers.J Clin Pharmacol. 2014; 54: 351-357
- A first-in-human clinical study with TRV734, an orally bioavailable G-protein-biased ligand at the μ-opioid receptor.Clin Pharmacol Drug Dev. 2020; 9: 256-266
- Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2019; 393: 778-790
- Effectiveness comparisons of G-protein biased and unbiased mu opioid receptor ligands in warm water tail-withdrawal and drug discrimination in male and female rats.Neuropharmacology. 2019; 150: 200-209
- The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats.Drug Alcohol Depend. 2018; 192: 158-162
- Abuse potential of biased mu opioid receptor agonists.Trends Pharmacol Sci. 2018; 39: 916-919
- Combination of naloxone with buprenorphine in humans.NIDA Res Monogr. 1989; 95: 485
- Toward a model of drug relapse: An assessment of the validity of the reinstatement procedure.Psychopharmacology. 2006; 189: 1-16
- Sex differences in opioid analgesia and addiction: Interactions among opioid receptors and estrogen receptors.Mol Pain. 2013; 9: 45
- Sex differences in neural mechanisms mediating reward and addiction.Neuropsychopharmacology. 2019; 44: 166-183
- Sex differences in locomotor effects of morphine in the rat.Pharmacol Biochem Behav. 2006; 85: 850-858
- Respiratory depression and brain hypoxia induced by opioid drugs: Morphine, oxycodone, heroin, and fentanyl.Neuropharmacology. 2019; 151: 219-226
- Central and peripheral mechanisms underlying physiological and drug-induced fluctuations in brain oxygen in freely-moving rats.Front Integr Neurosci. 2018; 12: 44
Article info
Publication history
Published online: February 24, 2020
Accepted:
February 13,
2020
Received in revised form:
February 13,
2020
Received:
June 11,
2019
Identification
Copyright
Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
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- Novel Application for G Protein–Biased Mu Opioid Receptor Agonists in Opioid Relapse PreventionBiological PsychiatryVol. 88Issue 12
- PreviewFor 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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