Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving
Open accessAbstract
Background Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. Here, we determined the effect of the TLR4 antagonist (+)-naltrexone (a μ-opioid receptor inactive isomer) on the time-dependent increases in cue-induced heroin seeking after withdrawal (incubation of heroin craving).Methods In an initial experiment, we trained rats for 9 hours per day to self-administer heroin (.1 mg/kg/infusion) for 9 days; lever presses were paired with a 5-second tone-light cue. We then assessed cue-induced heroin seeking in 30-minute extinction sessions on withdrawal day 1; immediately after testing, we surgically implanted rats with Alzet minipumps delivering (+)-naltrexone (0, 7.5, 15, 30 mg/kg/day, subcutaneous) for 14 days. We then tested the rats for incubated cue-induced heroin seeking in 3-hour extinction tests on withdrawal day 13.Results We found that chronic delivery of (+)-naltrexone via minipumps during the withdrawal phase decreased incubated cue-induced heroin seeking. In follow-up experiments, we found that acute injections of (+)-naltrexone immediately before withdrawal day 13 extinction tests had no effect on incubated cue-induced heroin seeking. Furthermore, chronic delivery of (+)-naltrexone (15 or 30 mg/kg/day) or acute systemic injections (15 or 30 mg/kg) had no effect on ongoing extended access heroin self-administration. Finally, in rats trained to self-administer methamphetamine (.1 mg/kg/infusion, 9 hours/day, 9 days), chronic delivery of (+)-naltrexone (30 mg/kg/day) during the withdrawal phase had no effect on incubated cue-induced methamphetamine seeking.Conclusions The present results suggest a critical role of TLR4 in the development of incubation of heroin, but not methamphetamine, craving.
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- Authors
- Theberge, F. R., Li, X., Kambhampati, S., Pickens, C. L., St. Laurent, R., Bossert, J. M., Baumann, M. H., Hutchinson, M. R., Rice, K. C., Watkins, L. R., & Shaham, Y.
- Affiliations
- National Institutes of Health (US)
- The University of Adelaide (AU)
- University of Colorado Boulder (US)
- Corresponding author
- Shaham, Yavin
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 73
- Issue
- 8
- Pages
- 729-737
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3615146
- OpenAlex
- W2038672096
- Cited by
- 119
- References
- 82
- Citations by year
- 2025: 5 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 18 · 2017: 9 · 2016: 8 · 2015: 11 · 2014: 14 · 2013: 4
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (K05DA024044, ZIADA000434)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Keywords
- TLR4, naltrexone, heroin craving, incubation of craving, opioid withdrawal, heroin self-administration, methamphetamine self-administration, mu-opioid receptor antagonist
- MeSH terms
- Animals, Conditioning, Operant, Cues, Heroin, Dose-Response Relationship, Drug, Drug Administration Schedule, Extinction, Psychological, Methamphetamine, Naltrexone, Narcotic Antagonists, Self Administration, Stereoisomerism, Time Factors, Infusion Pumps, Implantable, Behavior, Addictive, Toll-Like Receptor 4, Rats
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