Differential effects of opioid and adrenergic agonists on proliferation in a cultured cell line

Abstract

A novel clonal cell line transfected with the δ-opioid receptor (δ-OR) encoding gene was used to study agonist-activated regulation of cell proliferation. In this cell line, endogenous β2-adrenergic receptors (β2-ARs) are coexpressed with the exogenous δ-ORs. Upon individual acute treatments with morphine and procaterol (a selective β2-AR agonist), both the δ-OR and β2-AR are coupled to differential modulation of cyclic AMP (cAMP) levels in accord with the classical second messenger response patterns to these agonists in the normal cellular settings of the receptors. But chronic morphine activation of the δ-OR inhibits cellular proliferation, while chronic procaterol activation of the β2-AR stimulates it. Chronic treatment with the individual agonists is accompanied by differential activation of the mitogen-activated protein kinase (MAPK) isozymes, extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). The findings suggest that chronic β2-AR activation stimulates proliferation by interacting with the ERK signalling cascade independent of a cAMP-mediated pathway. In contrast to treatment with individual agonists, chronic dual agonist treatment suppresses procaterol-induced stimulation of ERK activity and stimulation of proliferation indicating that a cross-regulatory interaction occurs between the δ-OR and β2-AR signalling systems in the cells under these conditions.