Heterogeneity of the effects of naloxone on the endocrine control of lactation. The effects of the opiate antagonist, naloxone (2.0 mg/kg b.wt. ip), on the endocrine control of milk secretion were studied in 5-day lactating rats. In control animals (24 h after parturition) removal of the litter led to a marked rise in plasma prolactin (PRL), which rapidly returned to basal levels after 2 h. Administration of naloxone caused an increase in plasma PRL concentration only in lactating rats at the moment of parturition or in mothers separated for 3 h; such a treatment had no effect on PRL levels at 3 and 24 h after parturition. Similarly, an increase in circulating PRL levels was seen 30 min after naloxone administration in lactating rats receiving a single injection of oxytocin (0.4 U) while, 30 min later, the response to oxytocin was blunted, while there was no effect on PRL levels of lactating rats given ACTH (0.2 mg/kg b.wt. ip). The results show that, besides a direct effect on PRL secretion, naloxone in lactating rats has an indirect effect, mediated by the activity of the oxytocinergic system, through PRL suppression and, in turn, by a feedback effect of this hormone upon the hypothalamic-pituitary activity. In fact, the reduction in plasma PRL after naloxone is accompanied by an increase in plasma oxytocin. The fact that naloxone also acts on the LH-inhibiting factor (LIH) is demonstrated by the decrease of plasma LH levels after naloxone in lactating rats treated with a single injection of oxytocin (0.4 U). As a whole, the results suggest that opiate receptors may be involved in both the stimulation and inhibition of PRL and LH secretions in the rat. The results also suggest that the opioid system can mediate both the positive and the negative feedback of PRL upon the pituitary and that naloxone can affect the activity of the LH-inhibiting factor.