title: Effect of chronic delivery of the Toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving.
abstract: 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.
authors: Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors: Florence R
authors: FR
authors: Theberge
authors: Xuan
authors: X
authors: Li
authors: Sarita
authors: S
authors: Kambhampati
authors: Charles L
authors: CL
authors: Pickens
authors: Robyn
authors: R
authors: St Laurent
authors: Jennifer M
authors: JM
authors: Bossert
authors: Michael H
authors: MH
authors: Baumann
authors: Mark R
authors: MR
authors: Hutchinson
authors: Kenner C
authors: KC
authors: Rice
authors: Linda R
authors: LR
authors: Watkins
authors: Yavin
authors: Y
authors: Shaham
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005108:Extinction, Psychological / Q000187:drug effects; D003932:Heroin / Q000008:administration & dosage; D015918:Infusion Pumps, Implantable / Q000523:psychology; D008694:Methamphetamine / Q000008:administration & dosage; D009271:Naltrexone / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012646:Self Administration; D013237:Stereoisomerism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: D009292:Narcotic Antagonists; D051197:Toll-Like Receptor 4; D008694:Methamphetamine; D009271:Naltrexone; D003932:Heroin
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