Kappa opioids promote the proliferation of astrocytes via Gbetagamma and beta‐arrestin 2 dependent ERK/MAPK‐mediated pathways

Abstract

Seven‐ transmembrane receptors activate ERK/MAPK via G protein dependent and independent mechnanisms. Opioid receptors (ORs) modulate proliferation of immortalized and primary astrocytes via ERK. We examined κ OR‐induced, ERK‐mediated proliferation of rat immortalized and primary astrocytes to delineate participation of G protein vs. β‐arrestin (β‐arr). κ opioid agonist, U69,593, activated ERK by a rapid (min) initial stimulation that was sustained over 2 h and increased proliferation of immortalized and primary astrocytes as measured by bromodeoxyuridine labeling. κ agonist, MOM‐Sal‐B (a salvinorin derivative), induced ERK activation transiently (min) and did not affect proliferation of immortalized astrocytes suggesting that sustained ERK activity is required. In primary astrocytes, MOM‐Sal‐B elicited sustained ERK activity and proliferation. Transfection of immortalized astrocytes with cDNA of a Gβγ scavenger reduced ERK activaty by U69,593. Treatment of immortalized cells with siRNA indicated that ERK activation by U69,593 is β‐arr 2 dependent. The same inhibitors decreased MOM‐Sal‐B activation of ERK in immortalized cells. Gβγ scavenger or β‐arr 2 siRNA abolished proliferation of primary astrocytes induced by both κ opioids. The results suggest that Gβγ and β‐arr 2 dependent ERK activation pathways are required to elicit proliferation of primary astrocytes. Supported by NIH DA 05412