Interactions of kappa and delta opiates in the production of analgesia in animals and humans

Abstract

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-benzofuranacetamidemonohydrochloride) 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 μM bicuculline and picrotoxin or when potassium acetate-filled recording electrodes were used. Using potassium chloride-filled recording electrodes and in the presence of 30 μM 6-cyano-2,3-dihydro-7-nitroquinoxaline-2,3-dione and either 30 μMdl-2-amino-5-phosphonovaleric acid or 500 μM 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 μ-opioid receptor-selective agonistd-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. Doses of CI-977 1000–10,000 times higher than those which reduced the postsynaptic potentials had a naloxone-reversible hyperpolarizing action indistinguishable from that of DAGOL. Concentrations of bremazocine which reduced the excitatory postsynaptic potential antagonized the submaximal hyperpolarizing response to DAGOL.These results suggested that CI-977 acts as a potent agonist at a κ-opioid receptor located on presynaptic elements which release excitatory amino acids in the locus coeruleus. In contrast to CI-977, bremazocine acts as a weak agonist at these κ-opioid receptors and as a potent antagonist at μ-opioid receptors in the locus coeruleus.