Actions of opiate antagonists with selective receptor interactions in hemorrhagic shock

The broad-spectrum opiate antagonist naloxone has been shown previously to reverse hypotension and improve survival in hemorrhaged animals. Three new opiate antagonists with different receptor affinities and activities were utilized to investigate the role of the "mu"- and "kappa"-receptors in hemorrhagic shock. Cats in hemorrhagic shock (40 mm Hg for 150 min) and shamshock controls were given J-7747 (delta-antagonist), C-7000 (delta-antagonist and k-agonist) or MR-2266 (k-antagonist). Shock cats given the delta-antagonist J-7747 had a significantly higher final MABP than cats given vehicle as did the cats given C-7000, the delta-antagonist k-agonist. However, the k-antagonist MR-2266 did not result in a significantly greater MABP than untreated hemorrhaged cats. Both J-7747 and C-7000 significantly prevented the increase in plasma MDF activity observed in untreated shock cats, but MR-2266 did not. These results indicate that opiate receptors other than at k-receptor sites are involved in the pathophysiology of hemorrhagic shock. Our findings also introduce the possibility of the therapeutic use of opiate antagonist-analgesics that induce analgesia via the kappa receptor.