MULTIPLE OPIOID RECEPTORS IN ENDOTOXIC-SHOCK - EVIDENCE FOR DELTA-INVOLVEMENT AND MU-INTERACTION DELTA-INTERACTION INVIVO

The use of selective .delta. and .mu. opioid antagonists provided evidence that .delta. opioid receptors within the brain mediate the endogenous opioid component of endotoxic shock hypotension. The selectivity of these .delta. and .mu. antagonists was demonstrated by their differing effects on morphine analgesia and endotoxic [Escherichia coli] hypotension [in rats]. The .mu. antagonist .beta.-funaltrexamine, at doses that antagonized morphine analgesia, failed to alter shock; the .delta. antagonist M 154,129:[N,N-bisallyl-Tyr-Gly-Gly-.PSI.-(CH2S)-Phe-Leu-OH] reversed shock at doses that failed to block morphine analgesia. Therefore, selective .delta. antagonists may have therapeutic value in reversing circulatory shock without altering the analgesic actions of endogenous or exogenous opioids. Additional data revealed that prior occupancy of .mu. binding sites by irreversible opioid antagonists may allosterically attenuate the actions of antagonists with selectivity for .delta. binding sites. For endogenous opioid systems, this observation provides an opportunity to link in vivo physiological responses with receptor-level biochemical interactions.