Development of Tolerance to the Prolactin-Releasing Action of Morphine and Its Modulation by Hypothalamic Dopamine*

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Abstract
Exogenous and endogenous opioids are known to stimulate PRL release by the anterior pituitary. Morphine and the opioid peptides [D-Ala2, D-Leu5]enkephalin and β-endorphin have also been shown to decrease dopamine (DA) release by nerve terminals in the median eminence. The present study examined the ability of morphine sulfate (MS) to decrease DA turnover in the median eminence and increase plasma PRL concentrations in rats made tolerant to opioids by chronic treatment with MS. In naive rats, MS (10 mg/kg, sc) caused a mean increase in serum PRL of 79 ng/ml. After treatment with increasing doses of MS for 4 days, the same dose of MS caused an increase of only 18 ng/ml, indicating that tolerance to the PRL-releasing action of MS occurred. In the same animals, tolerance to the ability of MS to slow DA turnover in the median eminence also occurred, as demonstrated by an attenuation of the action of MS to decrease median eminence DA turnover. These results are consistent with the idea that MS and endogenous opioids increase the rate of release of PRL from the adenohypophysis by slowing the release of DA from the median eminence. This, in turn, results in a decrease in the inhibitory tone exerted on pituitary lactotropic cells and, consequently, a greater rate of PRL release. (Endocrinology 106: 1469, 1980)