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Antagonism of delta(2)-opioid receptors by naltrindole-5'-isothiocyanate attenuates heroin self-administration but not antinociception in rats.

Abstract
delta-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of delta-opioid receptors in vivo. This experiment assessed the contribution of delta-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible delta-antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A(50) values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33%. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90%. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40% while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (delta(2)) in a dose-dependent manner while having no effect on antinociception elicited after i.c. v. administration of [D-Pen(2),D-Pen(5)]-enkephalin (delta(1)) or [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (mu). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting delta(2)-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.
AuthorsT J Martin, S A Kim, D G Cannon, G M Sizemore, D Bian, F Porreca, J E Smith
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 294 Issue 3 Pg. 975-82 (Sep 2000) ISSN: 0022-3565 [Print] United States
PMID10945849 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Analgesics, Opioid
  • Isothiocyanates
  • Narcotic Antagonists
  • Oligopeptides
  • Receptors, Opioid, delta
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • deltorphin
  • naltrindole 5'-isothiocyanate
  • Naltrexone
  • Heroin
  • Enkephalin, D-Penicillamine (2,5)-
  • Cocaine
Topics
  • Analgesics, Opioid (pharmacology)
  • Animals
  • Cocaine (antagonists & inhibitors)
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (pharmacology)
  • Enkephalin, D-Penicillamine (2,5)- (pharmacology)
  • Heroin (antagonists & inhibitors)
  • Injections, Intraventricular
  • Isothiocyanates (pharmacology)
  • Male
  • Naltrexone (analogs & derivatives, pharmacology)
  • Narcotic Antagonists (pharmacology)
  • Oligopeptides (pharmacology)
  • Pain Measurement
  • Rats
  • Rats, Inbred F344
  • Receptors, Opioid, delta (antagonists & inhibitors)
  • Reinforcement, Psychology
  • Self Administration

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