Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving

Biol Psychiatry. 2013 Apr 15;73(8):729-37. doi: 10.1016/j.biopsych.2012.12.019. Epub 2013 Feb 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Addictive / drug therapy*
  • Conditioning, Operant / drug effects
  • Cues
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Extinction, Psychological / drug effects
  • Heroin* / administration & dosage
  • Infusion Pumps, Implantable / psychology
  • Methamphetamine / administration & dosage
  • Naltrexone / administration & dosage*
  • Naltrexone / pharmacology
  • Naltrexone / therapeutic use*
  • Narcotic Antagonists / pharmacology
  • Narcotic Antagonists / therapeutic use*
  • Rats
  • Self Administration
  • Stereoisomerism
  • Time Factors
  • Toll-Like Receptor 4 / antagonists & inhibitors*


  • Narcotic Antagonists
  • Toll-Like Receptor 4
  • Methamphetamine
  • Naltrexone
  • Heroin