Kappa-opioid restraint of oxytocin secretion: plasticity through pregnancy

Oxytocin neurone terminals display a powerful opioid-mediated auto-inhibitory mechanism which restrains secretory activity. In pregnancy, upregulation of this mechanism may underlie the accumulation of large stores of oxytocin in the pituitary. In the present study, conscious pregnant rats were cannulated to allow blood samples to be taken for measurement of oxytocin secretion in response to intravenous administration of cholecystokinin (CCK). In each rat, we measured the secretory response to CCK before and after administration of norbinaltorphine (norBNI), a selective kappa-opioid antagonist, or of naloxone, a relatively mu-selective antagonist. Throughout pregnancy, the stimulatory effect of CCK was enhanced by prior administration of norBNI. In pregnant rats norBNI also consistently increased basal oxytocin secretion, while naloxone had no effect, suggesting that in pregnancy there is active restraint of oxytocin secretion by endogenous opioids acting at kappa-receptors. However, in late pregnancy, between days 17 and 20, there was a significant reduction in the efficacy of norBNI in potentiating the oxytocin release in response to CCK, compared to its efficacy either in non-pregnant rats or in rats between days 8 and 13 of pregnancy. This suggests that in late pregnancy, endogenous kappa-opioid restraint is downregulated. In addition, the present results demonstrate an attenuation in the potency with which CCK evoked oxytocin release in late pregnancy. The attenuation was unrelated to opioid restraint at the level of the pituitary since it coincided with apparent desensitization of this auto-inhibitory mechanism.