AGONIST ACTIVATION OF DELTA-OPIOID RECEPTOR BUT NOT MU-OPIOID RECEPTOR POTENTIATES FETAL CALF SERUM OR TYROSINE KINASE RECEPTOR-MEDIATED CELL-PROLIFERATION IN A CELL-LINE-SPECIFIC MANNER

Activation by opioid receptors of cell proliferation was examined with fibroblast cell lines stably expressing either delta-opioid or mu-opi oid receptors. Addition of [D-Ala(2),n-Leu(5)]-enkephalin or [D-Pen(2) ,D-Pen(5)]-enkephalin to Chinese hamster ovary (CHO) cells transfected with delta-opioid receptor cDNA resulted in an agonist concentration- dependent potentiation of fetal calf serum (FCS)-stimulated cell proli feration. This potentiation by delta-opioid agonists was antagonized b y naloxone and was not observed with the kappa-opioid receptor selecti ve agonist U50,488 or the mu-opioid receptor selective agonist [D-Ala( 2),N-MePhe(4),Gly-ol(5)]-enkephalin. This delta-opioid agonist effect was not observed at FCS concentrations >0.1% and could be blocked by p retreating cells with pertussis toxin, indicating that G(i)/G(o) were involved in this action. In addition, delta-opioid agonists could pote ntiate CHO cell proliferation stimulated by those growth factors that are mediated by tyrosine kinase receptors (i.e., insulin, insulin-like growth factor 1, and fibroblast-derived growth factor b). This delta- opioid agonist potentiation of growth apparently was dependent on the level of delta-opioid receptors that were expressed and had cell-line selectivity. Activation of delta-opioid receptors expressed in Rat-1 o r NlH3T3 fibroblast did not result in a modulation of the cell growth induced by FCS or by growth factors. Interestingly, in CHO cells trans fected with mu-opioid receptor cDNA, activation with agonists did not produce a potentiation of FCS-stimulated proliferation. This lack of m u-opioid receptor effect was not due to the differences among CHO clon es. In a CHO cell line transfected with both delta-opioid receptor cDN A and mu-opioid receptor cDNA, activation of delta- but not mu-opioid receptors resulted in a potentiation of growth. These data suggest tha t delta- and mu-opioid receptors in CHO cells activate similar but div ergent second messenger pathways, resulting in the differential regula tion of cell growth.