kappa-Opioid tolerance and dependence
in cultures of dopaminergic midbrain neurons

by
Dalman FC, O'Malley KL
Department of Anesthesiology,
Washington University School of Medicine,
St. Louis,
Missouri 63110, USA.
J Neurosci 1999 Jul 15; 19(14):5750-7


ABSTRACT

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.
D2
CREB
JDTic
Enadoline
Dynorphin
Endomorphins
Kappa antagonism
Nor-binaltorphimine
Fentanyl and ketamine
Dynorphin and dopamine
Rapid opioid detoxification
Butorphanol versus morphine
Kappa receptors, dopamine d3, and cocaine
Kappa antagonists as future antidepressants?
Kappa opioids selectively control dopaminergic neurons
Depressive effects of the kappa-opioid receptor agonists
Kappa opioid antagonists as antidepressants : norbinaltorphimine
JDTic: an antidepressant, anxiolytic kappa-selective opioid receptor antagonist


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