The effect of morphine on cold-stimulated secretion of TSH and prolactin was studied in male rats, both in acute studies and after the chronic administration of morphine for 14 days (twice a day with increasing doses). The duration of the stimulatory effect of a single dose of morphine on secretion of prolactin was shorter (less than 2 hr) than its inhibitory effect on cold-stimulated secretion of TSH (over 2 hr). In the rats pretreated with morphine, a tolerance to the depressant effect of TSH of the challenge dose of morphine was seen at 2 hr but not at 1 hr after the injection. In contrast, a tolerance to the stimulatory effect of morphine on prolactin was seen at 1 hr after the acute dose of morphine. The minor alterations of the hypothalamic amine neurotransmitters and their metabolites did not correlate with the hormonal responses or to the development of tolerance.