Selective and interactive down-regulation of mu- and delta-opioid receptors in human neuroblastoma SK-N-SH cells

Y Baumhaker, M Gafni, O Keren and Y Sarne

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Israel.

Human neuroblastoma SK-N-SH cells, which contain both mu- and delta- opioid receptors, were grown under conditions that provided a mu:delta ratio of 1.5:1. Both receptors were down-regulated after 72 hr of exposure to 100 nM etorphine. Selective down-regulation was demonstrated using selective opioid agonists; the mu agonist Tyr-D-Ala2- Gly-(Me)Phe4-Gly-ol down-regulated mu- but not delta-opioid receptors, whereas prolonged exposure to the selective delta agonist D-Pen2,D-Pen5- enkephalin resulted in delta- but not mu-opioid receptor down- regulation. Morphine, which binds mu- as well as delta-opioid receptors, down-regulated both receptor subtypes. NG108-15 cells, which contain delta receptors exclusively, were also tested. NG108-15 cells did not exhibit delta-opioid receptor down-regulation when exposed to morphine. The discrepancy between the effect of chronic morphine treatment on delta receptors in SK-N-SH cells and in NG108-15 cells raised the question of whether the coexistence of mu receptors in the former allowed morphine to down-regulate delta receptors. The role of mu-opioid receptors in morphine-induced delta receptor down-regulation was studied by using the irreversible mu antagonist beta- funaltrexamine. Pretreatment of SK-N-SH cells with beta-funaltrexamine prevented down-regulation of delta receptors in response to chronic exposure to morphine but did not affect down-regulation of delta receptors in response to D-Pen2,D-Pen5-enkephalin. The experimental data indicate that morphine-induced delta-opioid receptor down- regulation is dependent on the presence of functional mu receptors in the same cell.

Volume 44, Issue 2, pp. 461-467, 08/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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