title: Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.
abstract: Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Powell
authors.forename: Noura S
authors.initials: NS
authors.lastname: Abul-Husn
authors.forename: Asha
authors.initials: A
authors.lastname: Jhamandas
authors.forename: Mary C
authors.initials: MC
authors.lastname: Olmstead
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Beninger
authors.forename: Khem
authors.initials: K
authors.lastname: Jhamandas
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004361:Drug Tolerance; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012201:Reward
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine