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A Subset of Kappa Opioid Ligands Bind to the Membrane Glucocorticoid Receptor in an Amphibian Brain

Zoology Department, Oregon State University, Corvallis, Oregon 97331

Address all correspondence and requests for reprints to: Frank L. Moore, Zoology Department, Oregon State University, Corvallis, Oregon 97331. E-mail: mooref{at}bcc.orst.edu

Previous studies demonstrated that a membrane receptor for glucocorticoids (mGR) exists in neuronal membranes from the roughskin newt (Taricha granulosa) and that this receptor appears to be a G protein-coupled receptor (GPCR). The present study investigated the question of whether this mGR recognizes nonsteroid ligands that bind to cognate receptors in the GPCR superfamily. To address this question, ligand-binding competition studies evaluated the potencies of various ligands to displace [³H]corticosterone (CORT) binding to neuronal membranes. Initial screening studies tested 21 different competitors and found that [³H]CORT binding was displaced only by dynorphin 1–13 amide (an endogenous -selective opioid peptide), U50,488 (a synthetic -specific agonist) and naloxone (a nonselective opioid antagonist). Follow-up studies revealed that the agonists bremazocine (BRE) and ethylketocyclazocine (EKC) also displaced [³H]CORT binding to neuronal membranes, but that U69,593 (a specific agonist) and nor-BNI (a specific antagonist) were ineffective. The K_i values measured for the opioid competitors were in the subnanomolar to low micromolar range and had the following rank-order: dynorphin > U50,488 > naloxone > BRE > EKC. Because these ligands displaced, at most, only 70% of [³H]CORT specific binding, it appears that some [³H]CORT binding sites are opioid insensitive. Kinetic analysis of [³H]CORT off-rates in the presence of U50,488 and/or CORT revealed no differences in dissociation rate constants, suggesting that there is a direct, rather than allosteric, interaction with the [³H]CORT binding site. In summary, these results are consistent with the hypothesis that the high-affinity membrane binding site for [³H]CORT is located on a opioid-like receptor.

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