Factors affecting morphine uptake into kidney slices.

The uptake of n-methyl¹⁴C]morphine by mouse kidney slices was saturable, reversible, temperature- and pH-dependent, and was inhibited by strong metabolic poisons and by structural analogs, thereby satisfying criteria for mediation by active transport processes. There were species differences: rat kidney cortex slices took morphine up at rates similar to those of mouse kidney, but guinea pig kidney cortex had lower uptake. Thin-layer chromatography (t.l.c.) of slice extracts after incubation with ¹⁴C]morphine did not indicate significant metabolism of morphine. Morphine efflux after equilibrium uptake from 30 nM or 10 μM initial medium levels required 20 min for 50 per cent of the ¹⁴C]morphine to exit. The uptake at 5 min was proportional to the equilibrium level at 30 min from 5 nM to 10 μM. No evidence for counter-transport was observed. Tissue/medium levels of 10–12 at 39–90 nM morphine (after 30 min at 37°) were reduced 50 per cent at pH 6.5 or at 20°, or by mitochondrial enzyme inhibitors, e.g. rotenone. Narcotic antagonists and analogs (methadone, nalorphine and levorphanol) and quinine also reduced the uptake of morphine from medium levels of 0.01 to 0.1 μM. However, at morphine concentrations above 10 μM, narcotic analogs or antagonists up to 50 μM did not inhibit uptake. Transport system inhibitors, quarternary bases, reducing agents and SH-oxidants also inhibited morphine uptake from 30 nM to 0.5 mM. Phloretin, phloridzin and atractyloside did not block uptake, while glucose, ouabain and NaF were very weak inhibitors. The results suggest that uptake of morphine in kidney slices involves SH groups and mitochondrial activity rather than glycolytic or ion-pump mechanisms. With a few exceptions, the characteristics and inhibitor sensitivity of morphine uptake by kidney slices and of amino acid uptake by brain slices appear similar.