The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter.
Meperidine has atypical opioid receptor agonist effects and shares some structural features with the phenyltropane (WIN) analogs of cocaine. In combination with 0.1 mg/kg naltrexone, meperidine produced cocaine-like discriminative stimulus effects in monkeys, whereas morphine was inactive. Both cocaine and meperidine inhibited [3H]dopamine uptake in chopped rat caudate putamen with comparable potencies; meperidine differed from cocaine in that its effects could be characterized as having predominantly a single high-affinity component. Morphine was not active in inhibiting [3H]dopamine uptake, indicating that the effect of meperidine was not via a classic mu-opioid receptor agonist action. Further, meperidine but not morphine displaced [3H]WIN 35,428 (2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane) binding. These data suggest that the actions of meperidine that are atypical of opioids are due to activity at the dopamine transporter. In addition, meperidine appears to interact predominantly with the high-affinity component of the dopamine transporter, and this high-affinity component may be the site of importance for the production of cocaine's behavioral effects.
Izenwasser
S
S
Division of Intramural Research, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Newman
A H
AH
Cox
B M
BM
Katz
J L
JL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008614:Meperidine / Q000494:pharmacology*; D008958:Models, Molecular; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009292:Narcotic Antagonists; D009294:Narcotics; D009419:Nerve Tissue Proteins; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D009271:Naltrexone; D009020:Morphine; D008614:Meperidine; D003042:Cocaine; D004298:Dopamine