MORPHINE: SITES OF ACTION IN GUANOSINE NUCLEOSIDE PATHWAY: 38

Abstract

Though cyclic GMP (cGMP) has been strongly implicated in morphine's analgetic action, the relationship between pharmacologic activity of morphine and brain levels of cGMP is not yet well understood. Here, we investigated effects of morphine on cGMP metabolism. Brain slices were incubated in tonometer at 37°C with Krebs-Ringer bicarbonate/glucose buffer, pH 7.35, constant flow of O2/CO2 (20:5) and 2.90 × 10−1 mM of substrate cGMP or 5'-GMP. Sequentially withdrawn aliquots of incubation mixture were analyzed by HPLC. Control brain slices yielded primary metabolic products, GMP, guanosine (GUS), guanine, xanthine, and inosine. Accumulation of guanosine agreed with evidence demonstrating that nucleoside phosphorylase is rate limiting. Chromatographic findings of inosine from samples of human brain slices incubated with cGMP or 5'-GMP as substrate extended our earlier report of 5'-GMP reductase activity in rat brain. No uric acid was detected. Morphine (1.46 × 10−2 mM) significantly reduced rate of cGMP and 5'-GMP metabolisms resulting in latent GUS accumulation substantially increased over control values. Our data suggest that morphine alters purine metabolism by inhibiting cGMP phosphodiesterase and 5'-nucleotidase. This may ultimately assist in establishing both biological significance of cGMP metabolites and multiple actions of morphine on the central nervous system. Supported by NIH/MBRS Grant RR 0809-12.