Kappa opioids exert a strong antiproliferative effect on PC12 rat pheochromocytoma cells

Pheochromocytomas synthesize several types of opioids and their receptors. Opioids affect the proliferation rate of normal and tumoral cells. We have previously shown that the PC12 rat pheochromocytoma cells synthesize multiple opioids. The aim of the present work was to study the effect of opioids on the proliferation of these pheochromocytoma cells. Thus, the effect of several opioid agonists and antagonists was examined on basal and EGF-induced PC12 cell proliferation. The kappa opioid agonists dynorphin A, U-69593, and U-50488 suppressed basal proliferation in a dose-dependent manner. The effect of kappa opioids was blocked by the general opioid antagonist naloxone and the selective kappa antagonist nor-binaltorphimine. Furthermore, both opioid antagonists given alone had a strong stimulatory effect, a findings suggesting that the proliferation of PC12 cells is under tonic inhibition by locally produced kappa opioids. Finally, the mu-opioid agonist DAGO and the delta and mu agonists DADLE and DSLET were ineffective.