The effect of lithium on morphine-induced analgesia in mice.

1. The effects of acute and chronic lithium (Li+) treatments on the antinociception caused by morphine were studied in mice using the tail-flick test. 2. Subcutaneous injection of morphine (10 mg/kg) caused significant antinociception. 3. Acute Li+ administration (0.05, 0.1, 0.3, 1, 5 and 10 mg/kg, i.p.) alone had no significant antinociceptive effect but changed morphine analgesia; low doses of Li+ (0.1, 0.3 and 1 mg/kg) were found to decrease the antinociception induced by morphine whereas higher doses of the drug (10 mg/kg) potentiated this effect. 4. The 6 day administration of Li+ with a serum level of 0.528 mM decreased the antinociceptive effect of morphine. 5. The effect of Li+ on morphine-induced analgesia persisted for 96 hr in spite of the fact that Li+ drinking was discontinued (the serum Li+ level decreased from 0.528 to 0.022 mM). 6. It has been reported that Li+ might change both the binding of opioids to their receptors and biosynthesis or release of endogenous opioids. There is also a considerable body of evidence which indicates that both Li+ and morphine affect phosphoinositide turnover, intracellular calcium content and cyclic AMP level. The interaction of two drugs may conceivably take place through these systems. 7. These data suggest that the biological effects of Li+ may exist at very much lower serum Li+ levels than the commonly accepted therapeutic range.