u-50488 and Shock

Subcutaneous injection of the potent, nonselective opioid antagonist diprenorphine inhibits the vasopressin response to acute hypovolemia. To determine if this inhibition is due to antagonism of opioid receptors in brain pathways that mediate volume control, we determined the vasopressin response to different stimuli when diprenorphine or other opiates were injected into the cerebral ventricles, the nucleus tractus solitarius (NTS), or the lateral parabrachial nucleus (PBN) of rats. We found that the vasopressin response to hypovolemia was inhibited by injection of diprenorphine into the cerebral ventricles at a dose too low to be effective when given subcutaneously. This response also was inhibited when a 20-fold lower dose of diprenorphine was injected into the PBN but not when it was injected into the NTS. The inhibitory effect of diprenorphine in the PBN was not attributable to a decrease in osmotic or hypovolemic stimulation and did not occur with osmotic or hypotensive stimuli. Injecting the PBN with equimolar doses of the mu antagonist naloxone, the delta antagonist ICI-154,129 or the kappa-1 agonist U-50,488H had no effect on basal or volume-stimulated vasopressin. We conclude that the inhibition of vasopressin by diprenorphine is due partially to action at a novel class of opioid receptors that transmit volume stimuli through the PBN.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Disease; Animals; Antihypertensive Agents; Brain; Cerebral Ventricles; Diprenorphine; Enkephalin, Leucine; Hemodynamics; Male; Naloxone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Sprague-Dawley; Shock; Solitary Nucleus; Stimulation, Chemical; Vasopressins

The kappa opioid agonists U50,488, bremazocine, ethylketazocine and tifluadom and the opioid antagonist naltrexone were examined alone and in combination with morphine in a squirrel monkey shock titration procedure, before and during chronic morphine administration. Before chronic morphine administration (prechronic phase), all opioids except naltrexone produced dose-dependent increases in median shock level when administered alone. When combined with a dose of morphine that increased median shock level to 90% of maximum (ED90), naltrexone, U50,488 and bremazocine completely antagonized the effects of morphine in most monkeys, whereas ethylketazocine and tifluadom partially antagonized the effects of this dose of morphine. After 10 weeks of daily morphine administration (chronic phase), the average ED90 for morphine was increased 1 log unit. In contrast, average ED50 values for U50,488, bremazocine and tifluadom were decreaed 1/4 to 1/2 log unit, whereas the average ED50 for ethylketazocine did not change from the prechronic to chronic phases. When combined with morphine during the chronic phase, naltrexone completely antagonized the effects of the morphine ED90 at approximately the same doses as during the prechronic phase. In contrast, antagonist activity decreased for U50,488 and bremazocine, increased for ethylketazocine and did not change consistently for tifluadom, compared with the prechronic phase. The present study demonstrates that chronic morphine administration alters both the agonist and antagonist activity of kappa opioids. Changes in antagonist activity of kappa opioids after chronic morphine administration may be explained by concurrent changes in their agonist potency and the extent to which their agonist effects are mu-mediated.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Drug Interactions; Drug Tolerance; Ethylketocyclazocine; Male; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Nociceptors; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Saimiri; Shock; Time Factors