Hypothalamic LH-RH release after acute and chronic treatment with morphine studied in a combined in vivo/in vitro model.

Rats were treated with the opiate agonist, morphine, and the release of luteinizing hormone-releasing hormone (LH-RH) from their hypothalami was studied in vitro. Within 16-24 h after morphine treatment, basal LH-RH release rates were observed to be higher compared to those from hypothalami derived from opiate-naive rats, suggesting that dependence had occurred in the neural mechanisms underlying LH-RH release. Maintenance of tissues exposed to morphine in vivo in medium containing morphine in vitro did not alter the increased basal release of LH-RH, but because this was significantly greater than control rates, tolerance is not believed to have occurred. Addition of the opioid antagonist naloxone in vitro resulted in a 220% increase in the release of LH-RH by hypothalami exposed to morphine for 48 h in vivo, whereas it caused a 50% reduction in LH-RH release from tissues exposed to morphine for 96 h in vivo. This latter result shows parallels with our previous finding that naloxone paradoxically decreases serum LH levels of chronically morphine-treated rats. In view of recent evidence for presynaptic feedback inhibitory effects operating on opioid neurons, it is suggested that, following chronic exposure to morphine, the opioid neurons which normally inhibit LH-RH neurons are inhibited; upon treatment with naloxone, they are disinhibited and release more opioid peptides which then act to switch off LH-RH neuronal activity.