MU-OPIOID RECEPTORS PARTICIPATE IN THE EXCITATORY EFFECT OF OPIATES IN THE HIPPOCAMPAL SLICE

Publisher Website
Google Scholar
Abstract
The effects of the opioid peptide morphiceptin and [N-MePhe3-D-Pro4]morphiceptin (PL017), both .mu.-receptor agonists, were examined by electrophysiological techniques in the rat hippocampal slice and ligand binding techniques in hippocampal membrane preparations. The electrophysiological actions of the .mu.-agonists were similar to those of the previously studied .delta.-receptor agonist [D-Ala2, D-Leu5]enkephalin. For a given size field excitatory postsynaptic potential the amplitude of both population spike and intracellular excitatory postsynaptic potential was increased by morphiceptin. These effects were concentration dependent and reversed by naloxone. The EC50 [median effective concentration] for morphiceptin was 1.6 .mu.M, which is consistent with the .mu.-selective binding properties of this peptide. Similar results were obtained with the more potent analog PL017. Morphiceptin and morphine had similar displacement profiles in competition experiments performed with hippocampal membranes and a variety of radioligands. In Tris buffer morphiceptin potently inhibited the binding of the .mu.-receptor marker [125I]FK 33,824 [D-Ala2,MePhe4, Met(O5-ol)]enkephalin] but displayed the expected shallow displacement isotherm against binding of the .delta.-receptor marker [125I] [D-Ala2,D-Leu5]enkephalin. A significant interaction of either morphiceptin or morphine with .kappa.-binding sites is improbable since neither agonist could fully displace binding of [3H]ethylketocyclazocine or [3H]diprenorphine. The potency of morphiceptin in displacing [3H]naloxone from .mu.-binding sites was reduced by inclusion of 100 mM NaCl or 100 .mu.M GTP in the assay. The Kd of morphiceptin for .mu.-binding sites in physiological saline was 0.78 .mu.M, comparable to its EC50 determined in electrophysiological experiments. The electrophysiological properties of opioid peptides in the hippocampal slice may be mediated by both .mu.- and .delta.-receptors. The low potency of alkaloids may be due to their weak efficacy at hippocampal .mu.-receptors.