Antinociceptive effect of clomipramine through interaction with serotonin 5-HT2 and 5-HT3 receptor subtypes.

Abstract

Tricyclic antidepressants are used in the treatment of various pain syndromes. The antidepressant clomipramine inhibits predominantly the reuptake of serotonin in the central nervous system. The mechanism of its analgesic effect is not fully understood. The AIM of the present study was to find experimentally any dose-effect dependence in the analgesic effect of clomipramine and the involvement of the 5-HT2 and 5-HT3 receptors in the mechanism of this effect. Fifty male Wistar rats were used in the study allocated to five groups (10 animals each): a saline treated control group, one positive control group treated with metamizole and three experimental groups treated with intraperitoneally administered clomipramine in doses of 5, 10 and 20 mg/kg bw, respectively. To study the role of 5-HT2 and 5-HT3 receptors in this effect we used another five groups (10 animals each): control, positive control and three experimental groups treated with clomipramine only, clomipramine and granisetrone and clomipramine and cyproheptadine, respectively. Three nociceptive tests were used: the hot plate test, analgesimeter and the acetic acid-induced writhing test. To gauge the antinociceptive action we used the increased latency in the hot plate test expressed as maximum possible effect % (%MPE), the increase in paw pressure to withdraw the hind paw in analgesimeter and decrease in the number of spinal cord writhes in the acetic acid test. Clomipramine in a dose of 20 mg/kg bw significantly increased the %MPE in hot plate test and the pressure to withdraw the hind paw in the analgesimeter when compared with the control. In the acetic acid test clomipramine decreased non-significantly the number of writhes compared with the controls. Granisetrone reduced non-significantly the antinociceptive effect of clomipramine in all tests. Cyproheptadine potentiated the analgesic effect of clomipramine in acetic acid test and decreased it significantly in the hot plate test. In analgesimeter cyproheptadine decreased significantly the paw pressure to withdraw the tested hind paw at 1 hour and non-significantly at 2 hours. Clomipramine in the dose of 20 mg/kg bw has a pronounced antinociceptive affect towards thermal and mechanical pain stimulation. The 5-HT2 and 5-HT3 receptor subtypes are very likely involved in the mechanism of this effect.