Antagonism of delta(2)-opioid receptors by naltrindole-5'-isothiocyanate attenuates heroin self-administration but not antinociception in rats.
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.
Martin
T J
TJ
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1803, USA. tjmartin@wfubmc.edu
Kim
S A
SA
Cannon
D G
DG
Sizemore
G M
GM
Bian
D
D
Porreca
F
F
Smith
J E
JE
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000037:antagonists & inhibitors; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D003932:Heroin / Q000037:antagonists & inhibitors*; D007276:Injections, Intraventricular; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement; D051381:Rats; D011916:Rats, Inbred F344; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D012646:Self Administration
D000701:Analgesics, Opioid; D017879:Isothiocyanates; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C059567:deltorphin; C064283:naltrindole 5'-isothiocyanate; D009271:Naltrexone; D003932:Heroin; D020881:Enkephalin, D-Penicillamine (2,5)-; D003042:Cocaine