NALTREXONE-INDUCED UP-REGULATION OF MU-OPIOID RECEPTORS ON 7315C CELLAND BRAIN MEMBRANES - ENHANCEMENT OF OPIOID EFFICACY IN INHIBITING ADENYLYL-CYCLASE

The effect of chronic naltrexone administration on the expression of m u opioid receptors on 7315c tumor cells was examined. Osmotic minipump s containing either saline or naltrexone were subcutaneously implanted into Buffalo rats that had been injected intraperitoneally with 7315c cells. Fourteen days after the pumps were implanted, 7315c tissue and brain tissue were removed and examined for their ability to bind [H-3 ]DAMGO and to respond to morphine (or DAMGO) and guanosine 5'-O-(3-thi otriphosphate) in an adenylyl cyclase assay. Naltrexone treatment caus ed a doubling in the density of [H-3]DAMGO binding sites in both whole brain membranes and the 7315c cell membranes. Naltrexone treatment ma y have slightly diminished the affinity of mu opioid receptors for [H- 3]DAMGO (by 1.5- to 2-fold), but the precision of the assay was inadeq uate to determine whether this difference was significant. Naltrexone treatment also had no effect on the potency or efficacy of guanosine 5 '-O-(3-thiotriphosphate) in diminishing [H-3]DAMGO binding to either w hole brain or 7315c cell membranes. The influence of naltrexone treatm ent on opioid inhibition of adenylyl cyclase activity was also investi gated in both tissues. In 7315c membranes, naltrexone treatment caused a 40% increase in the efficacy (maximal effect) of morphine but had n o effect on the potency (IC50) Of morphine in inhibiting forskolin-sti mulated adenylyl cyclase activity. In whole brain membranes from contr ol rats, DAMGO failed to affect significantly forskolin-stimulated ade nylyl cyclase. However, in whole brain membranes from naltrexone-treat ed rats, DAMGO caused a 30% inhibition of forskolin-stimulated adenyly l cyclase activity. Finally, naltrexone had no effect on either the po tency or efficacy of guanosine 5'-O-(3-thiotriphosphate) in inhibiting forskolin-stimulated adenylyl cyclase activity in either 7315c cell m embranes or whole brain membranes.