Temporal variation in drug interaction between lithium and morphine-induced analgesia

Chronobiol Int. 2006;23(3):675-82. doi: 10.1080/07420520600650745.


The administration-time-dependent aspects of the drug interaction between lithium and morphine-induced analgesia were studied using the mouse hot-plate test at six different times of day, each scheduled at 4 h intervals. Lithium treatment alone, in doses of 1 to 10 mmol/kg administered intraperitoneally (i.p.) did not significantly alter test latencies compared to the corresponding clock-time in saline-injected controls. Basal pain sensitivity and morphine-induced antinociceptive activity displayed significant circadian rhythms as assessed by the hot-plate response latencies, with higher values occurring during the nocturnal activity than during the daytime rest span. Acute administration of lithium, in a dose of 3 mmol/kg, 30 min prior to morphine dosing did not influence morphine-induced analgesia compared to all the clock-time test-matched morphine groups, except the 9 HALO (Hours After Lights On) one. There was a prominent potentiation of the morphine-induced antinociception at this biological time during combined drug treatment. The latter finding demonstrates that administration-time-dependent differences in drug-drug interactions need to be considered in both experimental designs and clinical settings.

MeSH terms

  • Analgesics / administration & dosage*
  • Animals
  • Circadian Rhythm / physiology*
  • Drug Administration Schedule
  • Drug Interactions
  • Lithium / administration & dosage*
  • Male
  • Mice
  • Morphine / administration & dosage*
  • Pain / drug therapy
  • Pain / physiopathology
  • Pain Measurement


  • Analgesics
  • Morphine
  • Lithium