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Notes: We have investigated the influence of endogenous opioids on oxytocin secretion during pregnancy. In blood-sampled consciousrats on days 18 and 21 of pregnancy plasma oxytocin concentration, measured by radioimmunoassay, was significantly increased compared to non-pregnant or post-partum rats. On days 15, 18 and 21 of pregnancy, but not in non-pregnant, early pregnant or post-partum rats, the opioid antagonist naloxone caused a significant increase in plasma oxytocin compared to vehicle injection, indicating activation of an endogenous opioid restraint over oxytocin secretion.Electrically stimulated neural lobes isolated from 16- and 21-day pregnant rats released more oxytocin than those from non-pregnant rats. However, naloxone (10−5 M) was less effective at potentiating, and the k-opioid agonist U50,488 (10−5 M) was less effective at inhibiting, stimulated release at the end of pregnancy than in non-pregnant rats suggesting desensitization of oxytocin nerve terminals to actions of endogenous opioids. Neural lobes from male rats drinking 2% saline for 4 days also showed desensitization of oxytocin nerve endings to naloxone.Neither neural lobe content of dynorphin A(1–8), an endogenous k-opioid, nor prodynorphin mRNA expression, measured by in situ hybridization histochemistry in the supraoptic nucleus altered during pregnancy. However, neural lobe content of Met5enkephalin significantly decreased by day 21 of gestation suggesting enhanced release. We conclude that an endogenous opioid, possibly a product of proenkephalin A in oxytocin cells may be responsible for auto-inhibition of oxytocin release during gestation, and that this mechanism desensitizes in late pregnancy at a time when other opioid inputs to the oxytocin neurons become activated to provide an overall increase in opioid restraint of the system. The changes in opioid input through pregnancy may be involved in initiation and regulation of oxytocin secretion at parturition. A similar opioid mechanism, but possibly involving dynorphin, could explain desensitization in saline drinking rats and indicates that desensitization may be a consequence of chronic activation of secretion from the oxytocin nerve terminals rather than a phenomenon peculiar to pregnancy.