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.
Dalman
F C
FC
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
O'Malley
K L
KL
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