Endogenous kappa-opioid systems in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release.
The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) was recently shown to potentiate certain overt withdrawal signs in morphine-dependent rats. The present study sought to further assess this phenomenon by examining the influence of nor-BNI treatment upon the conditioned place aversion associated with the naloxone-precipitated withdrawal syndrome. In addition, in vivo microdialysis studies were conducted in morphine-dependent rats to determine whether nor-BNI treatment can modify withdrawal-induced changes in basal dopamine (DA) release within the mesolimbic system. Rats were pretreated with either saline or a single dose of nor-BNI and then received ascending doses of morphine for 10 days. A withdrawal syndrome was then precipitated by the administration of naloxone (1 mg/kg SC). In rats which received chronic morphine injections, administration of naloxone produced a characteristic withdrawal syndrome and a marked aversion for an environment previously associated with naloxone-precipitated withdrawal. Nor-BNI treatment potentiated most overt signs of physical dependence. This treatment also resulted in a greater withdrawal-induced place aversion. Morphine-dependent rats exhibited a marked reduction in basal mesolimbic DA release. An even greater decrease in basal DA release was observed in nor-BNI treated rats. These results suggest that endogenous kappa-systems are important in the modulation of mesolimbic DA release and the accompanying place aversion which occurs during opiate withdrawal.
Spanagel
R
R
Department of Neuroendocrinology, Max-Planck-Institute of Psychiatry, Munich, Germany.
Almeida
O F
OF
Bartl
C
C
Shippenberg
T S
TS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D007276:Injections, Intraventricular; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009021:Morphine Dependence / Q000378:metabolism* / Q000523:psychology*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D012054:Reinforcement, Psychology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology*
D015306:Biogenic Monoamines; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D004298:Dopamine