pituitrin and bremazocine

The influence of kappa-opioid receptor agonists and antagonists on release of oxytocin and vasopressin was examined in isolated rat neurointermediate lobes. Electrically evoked release of oxytocin and vasopressin was concentration-dependently inhibited by the specific kappa-receptor agonist U69593, whereas bremazocine only inhibited the secretion of oxytocin markedly. Treatment with naloxone enhanced the evoked release of oxytocin significantly without effect on vasopressin secretion. The U69593-mediated inhibition of oxytocin release was abolished by naloxone, whereas that of vasopression was unaffected. Naloxone did not reverse the bremazocine-induced inhibition of hormone release. The data support the theory of an inhibiting endogenous control over oxytocin secretion and show that the release of oxytocin and vasopresin is differentially affected by the two K-receptor agonists.

Topics: Animals; Benzeneacetamides; Benzomorphans; Electric Stimulation; Female; In Vitro Techniques; Naloxone; Nerve Endings; Oxytocin; Pituitary Hormones, Posterior; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Vasopressins

Marked diuresis has previously been reported after administration of kappa opioid agonists. The present study shows that this effect is stereospecific; MR-2034 markedly increased urinary output over the dose range 0.08 to 1.25 mg/kg, whereas the opposite isomer, MR-2035, was markedly less potent. Bremazocine increased urinary output in Long-Evans hooded and Sprague-Dawley albino rats as well as lean and fatty Zucker rats. In the lean Zucker and the albino rats, bremazocine produced an inverted U-shaped diuretic dose-effect curve, an effect characteristic of kappa agonists with mu agonist activity. This pattern was not seen with the fatty Zucker rats or the Long-Evans hooded rats. The full kappa agonists bremazocine, ethylketazocine and U-50,488 increased urinary output under three different conditions of hydration: water loaded, normal hydration and water deprived. In contrast, the partial kappa agonists reliably only increase urinary output under the normal hydration condition. The diuretic effects of full and partial kappa agonists correlated with plasma vasopressin levels in water-deprived rats. The full kappa agonists (ethylketazocine, U-50,488, tifluadom and MR-2034) suppressed plasma vasopressin levels below the threshold of detectability of the radioimmunoassay, whereas the partial kappa agonists (nalorphine and butorphanol) suppressed vasopressin levels compared with control values but did not have the efficacy of the full kappa agonists. All these results support the hypothesis that kappa agonists produce their diuretic effect by suppression of plasma vasopressin levels.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Butorphanol; Cyclazocine; Diuresis; Drinking; Ethylketocyclazocine; Female; Male; Nalorphine; Pyrrolidines; Rats; Rats, Inbred Strains; Rats, Zucker; Receptors, Opioid; Receptors, Opioid, kappa; Stereoisomerism; Vasopressins; Water Deprivation

The effects of agonists at kappa, mu and delta opioid receptors were determined on vasopressin levels in water-deprived rats. Bremazocine and U-50, 488 (kappa agonists) markedly suppressed vasopressin levels, whereas morphine and methadone (mu agonists) and metkephamid (a mixed mu and delta agonist) did not suppress vasopressin levels. Likewise, clonidine, a potent diuretic in normally hydrated rats, did not clearly suppress vasopressin levels. Metkephamid was shown to have a modest diuretic effect in normally hydrated rats but not in water-deprived rats. The diuretic effects of bremazocine were blocked completely by simultaneous treatment with desmopressin, a synthetic vasopressin-like analog. Desmopressin also blocked the diuretic effect of a waterload, but only partially attenuated the diuretic effect of clonidine. These results support the hypothesis that kappa opioid agonists produce a diuretic effect by suppressing plasma levels of vasopressin, and at higher doses produce a pattern of urination similar to animals lacking vasopressin. By comparison, mu and delta opioid agonists have little effect on vasopressin levels in water-deprived rats.

Topics: Animals; Benzomorphans; Clonidine; Deamino Arginine Vasopressin; Diuresis; Dose-Response Relationship, Drug; Endorphins; Enkephalin, Methionine; Male; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Vasopressins

Several opioid antagonists have previously been shown to decrease drinking. The data have suggested that this was due to an antagonist action at kappa opioid receptors rather than mu or delta opioid receptors. Kappa agonists have a marked diuretic effect through suppression of vasopressin release. Antagonism of this kappa receptor-mediated effect can be used as an in vivo test for determining kappa-receptor antagonist activity. The potencies of opioid antagonists for antagonizing the diuretic effects of the kappa agonist bremazocine do not correlate directly with the potencies for decreasing deprivation-induced drinking. Further work should investigate the receptor specificity for effects on drinking and kappa-mediated diuresis.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Clonidine; Cyclazocine; Drinking; Ethylketocyclazocine; Naloxone; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Urination; Vasopressins