MORPHINE-TOLERANCE AND INHIBITION OF OXYTOCIN SECRETION BY KAPPA-OPIOIDS ACTING ON THE RAT NEUROHYPOPHYSIS

1. The present study investigated the mechanisms by which endogenous opioids regulate oxytocin secretion at the level of the posterior pituitary gland. Effects of the selective kappa-agonist U50,488 on oxytocin secretion were studied in urethane-anaesthetized lactating rats. Oxytocin secretion in response to electrical stimulation (0.5 mA, matched biphasic 1 ms pulses, 50 Hz, 60-180 pulses) of the neurohypophysial stalk was bioassayed on-line by measuring increases in intramammary pressure, calibrated with exogenous oxytocin. Intravenous (I.V.) U50,488 inhibited electrically stimulated oxytocin secretion, without affecting mammary gland sensitivity to oxytocin. The inhibition was dose related, with an ID50 of 441 (+194, -136) mug/kg and was naloxone reversible. Antagonism of endogenous beta-adrenoceptor activation by propranolol (1 mg/kg) reduced the potency of U50,488. The selective mu-agonist morphine (up to 5 mg/kg), had no effect on electrically stimulated oxytocin secretion, but depressed the mammary response to oxytocin. 2. In lactating rats given intracerebroventricular (I.C.V.) morphine infusion for 5 days to induce tolerance and dependence, I.V. U50,488 still inhibited electrically stimulated oxytocin secretion, but the ID50 was reduced to 170 (+78, -54) mug/kg; thus at the posterior pituitary the sensitivity of kappa-receptors is enhanced rather than reduced in morphine-tolerant rats, indicating the absence of cross-tolerance. In these rats, naloxone produced a large, sustained, fluctuating increase in intramammary pressure indicating morphine-withdrawal excitation of oxytocin secretion; I.V. U50,488 diminished this response, confirmed by radioimmunoassay, demonstrating the independence of mu- and kappa-receptors regulating oxytocin secretion. 3. In pregnant rats, I.C.V. infusion of morphine from day 17-18 of pregnancy delayed the start of parturition by 4 h, but did not significantly affect the progress of parturition once established, indicating tolerance to the inhibitory actions of morphine on oxytocin secretion in parturition, and lack of cross-tolerance to endogenous opioids restraining oxytocin in parturition. 4. Neurointermediate lobes from control and I.C.V. morphine-infused virgin rats were impaled on electrodes and perifused in vitro. Vasopressin and oxytocin release from the glands was measured by radioimmunoassay. Each gland was exposed to two periods of electrical stimulation (13 Hz, for 3 min). Naloxone (5 x 10(-6) M) was added before the second stimulation; half the lobes from each I.C.V. treatment were exposed to 5 x 10(-5) M morphine throughout. Oxytocin secretion in response to the first stimulation was similar in the four groups, indicating no acute effect of morphine, and no cross-tolerance from morphine to endogenous opioids released by electrical stimulation. In the presence of naloxone, stimulated oxytocin secretion was potentiated in all four treatment groups, again indicating lack of cross-tolerance to the endogenous opioids that restrain oxytocin secretion. Naloxone was more effective in potentiating oxytocin release from neurointermediate lobes of morphine-infused rats, consistent with increased endogenous kappa-opioid actions. For vasopressin, no significant actions of either morphine treatments or of endogenous neurohypophysial opioids were seen. 5. Thus two distinct opioid mechanisms regulate oxytocin secretion. Both mu- and kappa-agonists act centrally to inhibit the activity of oxytocin neurones but only kappa-agonists (and not mu-agonists) act at the secretory terminals. A decrease in the sensitivity to the central effects of mu-agonists can occur without affecting the terminal effects of kappa-agonists.