The effects of barbiturates upon the hemodynamic responses to intravenous methionine-enkephalin in dogs: modulation by the GABA complex.
In conscious animals, the intravenous administration of enkephalins increases heart rate (HR) and mean systemic arterial blood pressure (MAP); however, when given during barbiturate anesthesia, enkephalins reduce HR and MAP. We have investigated the potential role of the gamma-aminobutyric acid (GABA) complex (consisting of chloride-ion channel and binding sites for GABA, benzodiazepine, and barbiturate/picrotoxin) as the site of modulation of enkephalin responses by certain anesthetic agents in our chronically instrumented dog model. In our model, methionine-enkephalin (Met5-ENK) (35 micrograms/kg intravenously) increased HR and MAP, but following induction of general anesthesia with barbiturate (pentobarbital) or of sedation with benzodiazepine (diazepam), Met5-ENK produced vasodepressor responses despite differing levels of consciousness in the treated animals. Subsequent administration of picrotoxin restored pressor responses to Met5-ENK in the barbiturate-treated dogs, but not in those treated with benzodiazepine; picrotoxin did not alter the level of consciousness. Picrotoxin had no effect upon Met5-ENK responses in the conscious state. In contrast, alpha-chloralose, a convulsive anesthetic agent which does not appear to alter GABA complex activity, blunted but did not reverse pressor responses to Met5-ENK, despite causing a level of anesthesia similar to that produced by barbiturate. The observed pressor response to Met5-ENK during alpha-chloralose anesthesia was totally inhibited by naloxone, indicating that this response was still mediated by opiate receptors. Our data are compatible with modulation of enkephalin responses by GABA complex activity. Systemic enkephalins may generate afferent signals which may subsequently undergo GABA complex processing; the state of activation of the GABA complex may then determine whether systemic enkephalin signals are translated as vasopressor or vasodepressor responses.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002698:Chloralose / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004285:Dogs; D004744:Enkephalin, Methionine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D010424:Pentobarbital / Q000494:pharmacology*; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*
D002698:Chloralose; D003975:Diazepam; D004744:Enkephalin, Methionine; D010424:Pentobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A