Effect of imipramine on tolerance to morphine antinociception in the formalin test

In this study, the effect of imipramine on morphine antinociception in tole rant and non-tolerant mice in the formalin test, was investigated. Subcutan eous administration of different test doses of morphine (3, 6 and 9 mg/kg) and intraperitoneal injection of Lest doses of imipramine (10, 20 and 40 mg /kg) induced a dose-dependent antinociception in non-tolerant mice, both in the first and second phases of the formalin test. The combination of morph ine (1 mg/kg) with imipramine (10 mg/kg) showed a potentiated response in t he second phase of the test. Combination of a single dose of morphine (1.5 mg/kg) with lower doses of imipramine (2, 4 and 8 mg/kg) did not show poten tiation. The antinociceptive response of either morphine or morphine plus i mipramine was reduced by the opioid receptor antagonist naloxone (2 mg/kg). In order to induce tolerance, mice were treated subcutaneously with morphi ne (50 mg/kg) once daily for 3 days. On day 4, the antinociceptive effect o f test doses of morphine or imipramine were assessed. Tolerance to the resp onses of test doses of morphine (3, 6 and 9 mg/kg), but not imipramine (10, 20 and 40 mg/kg) in both phases of the test was observed. Administration o f lower dose of imipramine (4 mg/kg) before the test doses of morphine (3, 6 and 9 mg/kg) was not able to alter the expression of morphine tolerance. When imipramine was used during development of tolerance, either on days 1 and 2 or on days 2 and 3, the morphine tolerance in the second phase of the test was reduced. It is concluded that opioid receptor mechanism(s) may me diate the antidepressant-induced antinociception, however, imipramine may b e useful in inhibiting morphine tolerance.