A highly selective kappa-opioid receptor agonist, CI-977, reduces excitatory synaptic potentials in the rat locus coeruleus in vitro.
Intracellular recordings were made from neurons in a rat locus coeruleus slice preparation in vitro. A postsynaptic potential was evoked by electrical stimulation of afferents to the neurons. CI-977 ([5R-(5a,7a,8b)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec -8-yl[-4-benzofuranacetamide monohydrochloride) caused a depression of the evoked postsynaptic potential on locus coeruleus neurons. This action was reversed on washout. Bremazocine had a similar action on less than 50% of locus coeruleus neurons. Concentrations of CI-977 which depressed the postsynaptic potential did not affect either passive membrane conductance or a voltage-sensitive potassium current resembling IA. The depression of the excitatory postsynaptic potential caused by CI-977 remained in the presence of either 30 microM bicuculline and picrotoxin or when potassium acetate-filled recording electrodes were used. Using potassium chloride-filled recording electrodes and in the presence of 30 microM 6-cyano-2,3-dihydro-7-nitroquinoxaline-2,3-dione and either 30 microM DL-2-amino-5-phosphonovaleric acid or 500 microM kynurenic acid, CI-977 had no effect on the postsynaptic potential. The effects of CI-977 were reversed by 30-100 nM naloxone and 1-10 nM norbinaltorphimine but not by 1-10 nM naloxone. The hyperpolarizing response to the mu-opioid receptor-selective agonist D-Ala2,Nme Phe4,Gly-ol5 (DAGOL) was blocked by 1-10 nM naloxone but not by 1-100 nM norbinaltorphimine. The hyperpolarizing response to DAGOL was not affected by high doses of CI-977.(ABSTRACT TRUNCATED AT 250 WORDS)
Pinnock
R D
RD
Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge, U.K.
D000596:Amino Acids / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001575:Benzomorphans / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003864:Depression, Chemical; D004558:Electric Stimulation; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008125:Locus Coeruleus / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa; D013569:Synapses / Q000187:drug effects*
D000596:Amino Acids; D000700:Analgesics; D001572:Benzofurans; D001575:Benzomorphans; D001640:Bicuculline; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins; D008024:Ligands; D009270:Naloxone; D009271:Naltrexone; D010852:Picrotoxin; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; C027248:bremazocine; C067110:enadoline