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

A novel clonal cell line transfected with the delta-opioid receptor (delta- OR) encoding gene was used to study agonist-activated regulation of cell pr oliferation. In this cell line, endogenous beta(2)-adrenergic receptors (be ta(2)-ARs) are coexpressed with the exogenous delta-ORs. Upon individual ac ute treatments with morphine and procaterol (a selective beta(2)-AR agonist ), both the delta-OR and beta(2)-AR are coupled to differential modulation of cyclic AMP (cAMP) levels in accord with the classical second messenger r esponse patterns to these agonists in the normal cellular settings of the r eceptors. But chronic morphine activation of the delta-OR inhibits cellular proliferation, while chronic procaterol activation of the beta(2)-AR stimu lates it. Chronic treatment with the individual agonists is accompanied by differential activation of the mitogen-activated protein kinase (MAPK) isoz ymes, extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK ). The findings suggest that chronic beta(2)-AR activation stimulates proli feration by interacting with the ERK signalling cascade independent of a cA MP-mediated pathway. In contrast to treatment with individual agonists, chr onic dual agonist treatment suppresses procaterol-induced stimulation of ER K activity and stimulation of proliferation indicating that a cross-regulat ory interaction occurs between the delta-OR and beta(2)-AR signalling syste ms in the cells under these conditions.