Evidence for multiple mechanisms of kappa opioid tolerance in mesencephalic cultures.

Opioid tolerance limits the effectiveness of chronic opioid therapy. Kappa opioid tolerance in mesencephalic cultures has been established as a model system for evaluating neuronal mechanisms of tolerance. Our studies were carried out in primary cultures derived from the mesencephalon of rat embryos.

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.

A conserved proline in the hsp90 binding region of the glucocorticoid receptor is required for hsp90 heterocomplex stabilization and receptor signaling.

Studies of hsp90 in yeast have supported the notion that this chaperone plays a critical role in signaling by steroid receptors. One limitation to these studies is that yeast expressing hsp90 mutants may also be deficient in fundamental cellular functions of the chaperone required for steroid-dependent induction of transcription. In this work, we have prepared mutants of the glucocorticoid receptor (GR) that permit analysis of hsp90 binding and transcriptional activity in cells with normal chaperone function.