Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats.
Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and alleviate opioid tolerance and dependence. Our present studies in male Sprague-Dawley rats assessed the abuse potential of oxycodone+ultra-low-dose naltrexone (NTX) versus oxycodone alone. The lowest NTX dose (1 pg/kg/infusion), but not slightly higher doses (10 and 100 pg/kg/infusion), enhanced oxycodone (0.1 mg/kg/infusion) intravenous self-administration, suggesting a reduced rewarding potency per infusion. During tests of reinstatement performed in extinction conditions, co-self-administration of any of these three NTX doses significantly reduced drug-seeking precipitated by priming injections of oxycodone (0.25 mg/kg, s.c.), a drug-conditioned cue, or foot-shock stress. During self-administration on a progressive-ratio schedule, animals self-administering oxycodone (0.1 mg/kg/infusion)+NTX (1 pg/kg/infusion) reached a "break-point" sooner and showed a trend toward less responding compared to rats self-administering oxycodone alone (0.1 mg/kg/infusion). In the final experiment, the addition of ultra-low-dose NTX (10 pg/kg, s.c.) enhanced the acute stimulatory effect of oxycodone (1 mg/kg, s.c.), as well as locomotor sensitization produced by repeated oxycodone administration (7 x 1 mg/kg, s.c.). In summary, this work shows that ultra-low-dose NTX co-treatment augments the locomotor effects of oxycodone as it enhances opioid analgesia, but reduces oxycodone's rewarding potency and subsequent vulnerability to relapse.
Leri
Francesco
F
Department of Psychology, University of Guelph (Guelph, ON), Canada N1G 2W1. fleri@uoguelph.ca
Burns
Lindsay H
LH
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D003463:Cues; D004597:Electroshock; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010098:Oxycodone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration
D009292:Narcotic Antagonists; D009294:Narcotics; D009271:Naltrexone; D010098:Oxycodone