Naltrindole, a selective delta-opioid receptor antagonist, potentiates the lethal effects of cocaine by a central mechanism of action.
The potentiation of the toxic and lethal effects of cocaine by the selective delta-opioid receptor antagonist naltrindole was explored in unrestrained, unanesthetized rats that received a continuous intravenous infusion of cocaine until death. The lethal dose of cocaine was lowered dose dependently in animals administered naltrindole intracisternally (3.0-30 microg), but not intravenously (30-300 microg). There was also a decrease in the lethal dose of cocaine following an injection of the nonselective opioid antagonist naltrexone, but not naloxone. However, the seizure-producing dose of cocaine was decreased dose dependently in rats that received naltrindole, regardless of the route of administration, naloxone, or naltrexone. In contrast, the effect of cocaine on heart rate was altered only by centrally administered naltrindole or intravenous naltrexone, with a dose of 30 microg naltrindole and 10 mg/kg naltrexone abolishing the bradycardic effect of cocaine. Despite this, neither naltrindole nor naltrexone changed the hypertensive effect of cocaine. Higher doses of naltrindole (100 microg i.c.) produced significant increases in heart rate and mean arterial pressure and were not tested in combination with cocaine. Because the lethal dose of cocaine was reduced only when naltrindole was administered intracisternally, the potentiation of the lethal effects of cocaine by naltrindole is through a central mechanism of action that may involve changes in cardiovascular function.
Patterson
A B
AB
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Gordon
F J
FJ
Holtzman
S G
SG
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D002946:Cisterna Magna; D003042:Cocaine / Q000633:toxicity*; D004357:Drug Synergism; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007267:Injections; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D009294:Narcotics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000503:physiopathology
D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D009270:Naloxone; D009271:Naltrexone; C055382:naltrindole; D003042:Cocaine