PT  - JOURNAL ARTICLE
AU  - Dalman, Friedrich C.
AU  - O’Malley, Karen L.
TI  - κ-Opioid Tolerance and Dependence in Cultures of Dopaminergic Midbrain Neurons
AID  - 10.1523/JNEUROSCI.19-14-05750.1999
DP  - 1999 Jul 15
TA  - The Journal of Neuroscience
PG  - 5750--5757
VI  - 19
IP  - 14
4099  - http://www.jneurosci.org/content/19/14/5750.short
4100  - http://www.jneurosci.org/content/19/14/5750.full
SO  - J. Neurosci.1999 Jul 15; 19
AB  - Repeated cocaine exposure upregulates κ opioids and their receptors in the mesocorticolimbic system; the ensuing κ-mediated dysphoria appears to contribute to addiction and withdrawal. As a potential rehabilitation strategy to reverse cocaine-induced κ sensitization, the present study used tritiated dopamine release assays to examine the induction of κ-opioid tolerance in cultured mesencephalic neurons. Administration of the κ agonist U69,593 inhibited tetrodotoxin-sensitive, spontaneous (EC50 = 1.5 nm), and potassium-stimulated (EC50 = 10 nm) release. These effects were blocked by pertussis toxin and by the κ antagonist nor-binaltorphimine. The 2 d agonist exposure (1 μm) 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 κ-receptor signaling mechanisms and to dependence. In the stimulated release assay, attenuation of κ 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 (t½ = 20 hr). In the spontaneous release assay, attenuation of κ-opioid signaling occurred slowly (t½ = 22 hr), and resensitization after a 144 hr exposure was rapid (t½ < 1 hr). κ-Opioid dependence was observed after 144 hr of U69,593 exposure. Thus multiple mechanisms of adaptation to κ-opioid exposure occur in mesocorticolimbic neurons. These data support the idea that the administration of κ opioids might facilitate drug rehabilitation.