ici-154129 and Shock--Septic

The use of selective delta and mu opioid antagonists has 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 upon morphine analgesia and endotoxic hypotension. The mu antagonist beta-funaltrexamine, at doses that antagonized morphine analgesia, failed to alter shock, whereas the delta antagonist M 154,129: [N,N-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH] (ICI) 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.

Topics: Allosteric Regulation; Animals; Blood Pressure; Enkephalin, Leucine; Macromolecular Substances; Male; Naltrexone; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Shock, Septic

Using antagonists with selectivity for the delta (ICI 154,129) and mu (beta-funaltrexamine) binding sites, evidence was obtained to indicate that delta receptors within the brain mediate the endogenous opioid component of endotoxic hypotension. The therapeutic actions of intravenous ICI 154,129 were dose related, with effective doses between 15-60 mg/kg. Evidence for a functional interaction between mu and delta binding sites was obtained: prior occupancy of the mu binding site by beta-funaltrexamine prevented the usual therapeutic response to the delta antagonist ICI 154,129 in endotoxemic rats. These data indicate that mu and delta binding sites may be a part of the same macromolecular complex which interact through allosteric coupling.

Topics: Animals; Blood Pressure; Enkephalin, Leucine; Heart Rate; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pulse; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Shock, Septic