Opiates suppress a resting sodium-dependent inward current and activate an outward potassium current in locus coeruleus neurons.
The opioid peptide met-enkephalin (met-ENK) produces an outward current with an increase in input conductance in locus coeruleus (LC) neurons. This current has been attributed to an opening of potassium channels. However, the opioid-induced current tends to reverse at potentials more negative than the expected potassium reversal potential (EK) or does not reverse at all. Since lack of reversal can occur if there is a simultaneous increase in one conductance and a decrease in a second conductance, we tested the possible contribution of a second conductance to the opioid-induced outward current in LC neurons. Biochemically, opiates inhibit adenylate cyclase in LC neurons and cAMP-active agents produce a sodium-dependent inward current in these neurons. This current is also present at rest, as sodium substitution hyperpolarizes LC neurons. By inhibiting adenylate cyclase, could opiates be turning off this current? To evaluate this possibility, we used intracellular voltage-clamp technique in rat LC slices, and studied the effect of sodium substitution on the opiate response. Replacement of external sodium (80%) with Tris or choline caused (1) an outward current with a decrease in input conductance and (2) an approximately 50% decrease in the met-ENK-induced outward current with a shift in its reversal potential toward EK. Extracellular Ba2+, a K+ channel blocker, also partially reduced the opiate response, but it shifted its reversal potential away from EK. The met-ENK-induced outward current was almost totally abolished by combined sodium substitution and extracellular Ba2+ in an additive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
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Alreja
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Aghajanian
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002794:Choline / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004553:Electric Conductivity; D004744:Enkephalin, Methionine / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D012964:Sodium / Q000494:pharmacology*; D014325:Tromethamine / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D015221:Potassium Channels; D014325:Tromethamine; D001464:Barium; D004744:Enkephalin, Methionine; D012964:Sodium; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D002794:Choline