Naltrexone-induced upregulation of mu opioid receptors on 7315c cell and brain membranes: enhancement of opioid efficacy in inhibiting adenylyl cyclase.
The effect of chronic naltrexone administration on the expression of mu opioid receptors on 7315c tumor cells was examined. Osmotic minipumps 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 [3H]DAMGO and to respond to morphine (or DAMGO) and guanosine 5'-O-(3-thiotriphosphate) in an adenylyl cyclase assay. Naltrexone treatment caused a doubling in the density of [3H]DAMGO binding sites in both whole brain membranes and the 7315c cell membranes. Naltrexone treatment may have slightly diminished the affinity of mu opioid receptors for [3H]DAMGO (by 1.5- to 2-fold), but the precision of the assay was inadequate 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 [3H]DAMGO binding to either whole brain or 7315c cell membranes. The influence of naltrexone treatment on opioid inhibition of adenylyl cyclase activity was also investigated in both tissues. In 7315c membranes, naltrexone treatment caused a 40% increase in the efficacy (maximal effect) of morphine but had no effect on the potency (IC50) of morphine in inhibiting forskolin-stimulated adenylyl cyclase activity. In whole brain membranes from control rats, DAMGO failed to affect significantly forskolin-stimulated adenylyl cyclase. However, in whole brain membranes from naltrexone-treated rats, DAMGO caused a 30% inhibition of forskolin-stimulated adenylyl cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Izenwasser
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Weems
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D004745:Enkephalins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; D000262:Adenylyl Cyclases