Evidence for a dual mechanism in the anesthetic action of an opioid peptide.
Loss of righting reflex (LRR) produced by various concentrations of the leucine-enkephalin analog BW831c (TYR.D-ALA.GLY.PHE.D-LEU.NHEt.HCI) was determined in amphibia at 1 atm and 120 atm of helium. EC50 for LRR was 22.1 +/- 1.6 microM and 44 +/- 6.9 microM, respectively. The octanol/water partition coefficient (P) was 26 +/- 3.6, suggesting that this peptide is sufficiently lipid soluble for a classic Meyer-Overton type of anesthetic action. The ratio (EC50 at 120 atm)/(EC50 at 1 atm) for the peptide (2.0 +/- 0.31) was essentially the same as that for the long-chain alcohol, octanol (1.8 +/- 0.08), and similar to those reported for phenobarbital and the gaseous anesthetics. Thus, peptide-induced LRR was reversible by pressure. Peptide-induced LRR also was completely reversible by naloxone, whereas octanol-induced LRR was unaffected by up to 100 microM naloxone. These findings are consistent with a dual mechanism of anesthetic action for this peptide: one, an opiate receptor-specific mechanism, reversible with the specific opiate antagonist, naloxone; the other, a nonspecific mechanism, related to lipid solubility and reversible with the application of the physical agent, pressure.
Dodson
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Miller
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D020003:1-Octanol; D000701:Analgesics, Opioid; D000777:Anesthetics / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001274:Atmospheric Pressure; D001392:Azocines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives*; D008055:Lipids; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D000442:Octanols / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011894:Rana pipiens; D011957:Receptors, Opioid / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012995:Solubility; D013997:Time Factors
D000701:Analgesics, Opioid; D000777:Anesthetics; D001392:Azocines; D008055:Lipids; D009292:Narcotic Antagonists; D000442:Octanols; D011957:Receptors, Opioid; D009270:Naloxone; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C023668:2-Ala-5-N-Et-Leu-enkephalinamide; D020003:1-Octanol; C035969:quadazocine