SELECTIVE AND INTERACTIVE DOWN-REGULATION OF MU-OPIOID AND DELTA-OPIOID RECEPTORS IN HUMAN NEUROBLASTOMA SK-N-SH CELLS

Human neuroblastoma SK-NS-SH cells, which contain both mu- and delta-o pioid receptors, were grown under conditions that provided a mu:delta ratio of 1.5:1. Both receptors were down-regulated after 72 hr of expo sure to 100 nm etorphine. Selective down-regulation was demonstrated u sing selective opioid agonists; the mu agonist Tyr-D-Ala 2-Gly-(Me)Phe 4-Gly-ol down-regulated mu- but not delta-opioid receptors, whereas pr olonged exposure to the selective delta agonist D-Pen 2 D-Pen 5-enkeph alin resulted in delta- but not mu-opioid receptor down-regulation. Mo rphine, which binds mu- as well as delta-opioid receptors, down-regula ted both receptor subtypes. NG108-15 cells, which contain delta recept ors exclusively, were also tested. NG108-15 cells did not exhibit delt a-opioid receptor down-regulation when exposed to morphine. The discre pancy between the eff ect of chronic morphine treatment on delta recep tors in SK-NS-SH cells and in NG108-15 cells raised the question of wh ether the coexistence of mu receptors in the former allowed morphine t o down-regulate delta receptors. The role of mu-opioid receptors in mo rphine-induced delta receptor down-regulation was studied by using the irreversible mu antagonist beta-funaltrexamine. Pretreatment of SK-NS -SH cells with beta-funaltrexamine prevented down-regulation of delta receptors in response to chronic exposure to morphine but did not affe ct down-regulation of delta receptors in response to D-Pen 2 D-Pen5-en kephalin. The experimental data indicate that morphine-induced delta-o pioid receptor down-regulation is dependent on the presence of functio nal mu receptors in the same cell.