Opposing Tonically Active Endogenous Opioid System Modulating the Mesolimbic Dopamine Reward Pathway


Opioids, prototypical drugs of abuse, exert marked effects on motivation. µ- and ∂-opioid receptor agonists function as positive reinforcers. In contrast, k-opioid receptor agonists induce aversive and dysphoric states. The conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the motivational effects of highly selective opioids and the technique of in-vivo microdialysis was applied to assess the neurochemical basis of such effects. Conditioned place preference was obtained by microinjection of the.µ-opioid receptor agonist DAGO into the ventral tegmental area (VTA), (the site of origin of the A10 dopamine neurons), but not when injected into the nucleus accumbens (NAC) and in further forebrain areas. In contrast, conditioned place aversion was obtained by microinjection of the specific k-opioid receptor agonists U-50,488 and/or U-69593 into the VTA, NAC, medial frontal cortex and lateral hypothalamus; microinjection of these and k-agonists into the substantia nigra and the caudatus putamen were ineffective. Microinjection of DAGO into the VTA resulted in significant increase in the release of dopamine (DA) and its metabolism in the NAC. However, DAGO infusions into the NAC via the microdialysis probe did not affect release of DA or its metabolites. The selective blockade of µ-receptors by CTOP within the VTA produced significant decrease of DA basal release. In contrast, CTOP infusions into the NAC were without effect. The selective k-agonist U 69853 microinjected into the VTA did not change the DA overflow. In contrast, U 69853 infusion into the NAC resulted in a dose-dependent significant decrease in DA release. Infusions of the k-antagonist nor-BNI into the NAC dose-dependently increased basal DA release within the NAC, but it was ineffective when injected into the VTA. These data demonstrate that the same mesolimbic pathway is modulated by two opposing tonically active endogenous opioid systems. The concerted action of the two systems (possibly a ß-endorphin system in the VTA and a dynorphin presynaptically located dynorphin system in the NAC) allows the maintenance of basal mesolimbic DA release.


Nucleus Accumbens Ventral Tegmental Area Conditioned Place Preference Place Preference Aversive Effect 
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Copyright information

© Springer-Verlag Wien 1995

Authors and Affiliations

  • A. Herz
    • 1
  1. 1.Department of NeuropharmacologyMax-Planck-Institute for PsychiatryMartinsriedGermany

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