Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats

J Pharmacol Exp Ther. 2002 Feb;300(2):588-96. doi: 10.1124/jpet.300.2.588.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Conditioning, Operant / drug effects
  • Drug Tolerance
  • Injections, Intraperitoneal
  • Injections, Spinal
  • Male
  • Mice
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Naloxone / administration & dosage
  • Naloxone / pharmacology*
  • Narcotic Antagonists / administration & dosage
  • Narcotic Antagonists / pharmacology*
  • Pain Measurement / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Reward*

Substances

  • Analgesics, Opioid
  • Narcotic Antagonists
  • Naloxone
  • Morphine