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Vol. 59, Issue 4, 774-783, April 2001

Interaction of Co-Expressed µ- and delta -Opioid Receptors in Transfected Rat Pituitary GH3 Cells

Nancy A. Martin and Paul L. Prather

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

µ- and delta -Opioid agonists interact in a synergistic manner to produce analgesia in several animal models. Additionally, receptor binding studies using membranes derived from brain tissue indicate that interactions between µ- and delta -opioid receptors might be responsible for the observation of multiple opioid receptor subtypes. To examine potential interactions between µ- and delta -opioid receptors, we examined receptor binding and functional characteristics of µ-, delta -, or both µ- and delta -opioid receptors stably transfected in rat pituitary GH3 cells (GH3MOR, GH3DOR, and GH3MORDOR, respectively). Saturation and competition binding experiments revealed that coexpression of µ- and delta -opioid receptors resulted in the appearance of multiple affinity states for µ- but not delta -opioid receptors. Additionally, coadministration of selective µ- and delta -opioid agonists in GH3MORDOR cells resulted in a synergistic competition with [3H][D-Pen2,5]enkephalin (DPDPE) for delta -opioid receptors. Finally, when equally effective concentrations of [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) and two different delta -opioid agonists (DPDPE or 2-methyl-4aalpha -(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha -octahydroquinolino-[2,3,3-g]-isoquinoline; TAN67) were coadministered in GH3MORDOR cells, a synergistic inhibition of adenylyl cyclase activity was observed. These results strongly suggest that cotransfection of µ- and delta -opioid receptors alters the binding and functional characteristics of the receptors. Therefore, we propose that the simultaneous exposure of GH3MORDOR cells to selective µ- and delta -opioid agonists produces an interaction between receptors resulting in enhanced receptor binding. This effect is translated into an augmented ability of these agonists to inhibit adenylyl cyclase activity. Similar interactions occurring in neurons that express both µ- and delta -opioid receptors could explain observations of multiple opioid receptor subtypes in receptor binding studies and the synergistic interaction of µ- and delta -opioids in analgesic assays.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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