kappa-Opioid tolerance and dependence in cultures of dopaminergic midbrain neurons.
Repeated cocaine exposure upregulates kappa opioids and their receptors in the mesocorticolimbic system; the ensuing kappa-mediated dysphoria appears to contribute to addiction and withdrawal. As a potential rehabilitation strategy to reverse cocaine-induced kappa sensitization, the present study used tritiated dopamine release assays to examine the induction of kappa-opioid tolerance in cultured mesencephalic neurons. Administration of the kappa agonist U69,593 inhibited tetrodotoxin-sensitive, spontaneous (EC(50) = 1.5 nM), and potassium-stimulated (EC(50) = 10 nM) release. These effects were blocked by pertussis toxin and by the kappa antagonist nor-binaltorphimine. The 2 d agonist exposure (1 microM) caused a shift in the U69,593 dose-response curve that was greater in the potassium-stimulated paradigm (140-fold) than in the spontaneous release assay (sixfold). These results were attributable to the attenuation of kappa-receptor signaling mechanisms and to dependence. In the stimulated release assay, attenuation of kappa signaling caused by 4 hr of U69,593 exposure recovered with a half-life of 1.1 hr, whereas attenuation after 144 hr of exposure recovered slowly (t(1/2) = 20 hr). In the spontaneous release assay, attenuation of kappa-opioid signaling occurred slowly (t(1/2) = 22 hr), and resensitization after a 144 hr exposure was rapid (t(1/2) < 1 hr). kappa-Opioid dependence was observed after 144 hr of U69,593 exposure. Thus multiple mechanisms of adaptation to kappa-opioid exposure occur in mesocorticolimbic neurons. These data support the idea that the administration of kappa opioids might facilitate drug rehabilitation.
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Dalman
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O'Malley
D000700:Analgesics / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D044482:Benzeneacetamides; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D005333:Fetus; D007700:Kinetics; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D037342:Pertussis Toxin; D011188:Potassium / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000700:Analgesics; D044482:Benzeneacetamides; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D010566:Virulence Factors, Bordetella; C051844:norbinaltorphimine; D013779:Tetrodotoxin; D009271:Naltrexone; D037342:Pertussis Toxin; C045444:U 69593; D011188:Potassium; D004298:Dopamine