Effect of Imipramine on Tolerance to Morphine Antinociception in the Formalin Test

Abstract

In this study, the effect of imipramine on morphine antinociception in tolerant and non-tolerant mice in the formalin test, was investigated. Subcutaneous administration of different test doses of morphine (3, 6 and 9 mg/kg) and intraperitoneal injection of test 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 morphine (1 mg/kg) with imipramine (10 mg/kg) showed a potentiated response in the 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 potentiation. The antinociceptive response of either morphine or morphine plus imipramine was reduced by the opioid receptor antagonist naloxone (2 mg/ kg). In order to induce tolerance, mice were treated subcutaneously with morphine (50 mg/kg) once daily for 3 days. On day 4, the antinociceptive effect of test doses of morphine or imipramine were assessed. Tolerance to the responses 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 of 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 mediate the antidepressant-induced antinociception, however, imipramine may be useful in inhibiting morphine tolerance.

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

“…Anxiety-related behavior was measured at least 24 h after the last treatment. that imipramine produces a significant acute analgesic effect at 10-40 mg/kg in the formalin test (Sabetkasai et al, 1999;Zarrindast et al, 2000aZarrindast et al, , 2003, 10-15 mg/kg in the hot-plate test (Ghelardini et al, 2000;Sahebgharani and Zarrindast, 2001), and 20-30 mg/kg against a neuropathic pain-like state (Zarrindast et al, 2000b). It also induces an antidepressive effect at 10-32 mg/kg in the forced swimming test (Clenet et al, 2001;David et al, 2003;Rojas-Corrales et al, 2003).…”