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-opioid receptors. Addition of [D-Ala2, D-Leu5]-enkephalin or [D-Pen2,D-Pen5]-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 proliferation. This potentiation by delta-opioid agonists was antagonized by naloxone and was not observed with the kappa-opioid receptor selective agonist U50,488 or the mu-opioid receptor selective agonist [D-Ala2,N-MePhe4, Gly-ol5]-enkephalin. This delta-opioid agonist effect was not observed at FCS concentrations > 0.1% and could be blocked by pretreating cells with pertussis toxin, indicating that Gi/Go were involved in this action. In addition, delta-opioid agonists could potentiate 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 or NIH3T3 fibroblast did not result in a modulation of the cell growth induced by FCS or by growth factors. Interestingly, in CHO cells transfected with mu-opioid receptor cDNA, activation with agonists did not produce a potentiation of FCS-stimulated proliferation. This lack of mu-opioid receptor effect was not due to the differences among CHO clones. In a CHO cell line transfected with both delta-opioid receptor cDNA and mu-opioid receptor cDNA, activation of delta-but not mu-opioid receptors resulted in a potentiation of growth. These data suggest that delta- and mu-opioid receptors in CHO cells activate similar but divergent second messenger pathways, resulting in the differential regulation of cell growth.