In the present study, the effects of intracerebroventricular (ICV) administration of normal saline (control), histamine, mepyramine (a histamine H1-receptor antagonist) and ranitidine (a histamine H2-receptor antagonist) were investigated on the formalin-induced pain in rabbits. Subcutaneous (SC) injection of a formalin (100 μl, 5%) solution into the ventral surface of the right hind paw was performed, and the time durations spent licking and biting the injected paw were measured in 10 min blocks for 1 h. The SC injection of formalin produced a short-lasting (10 min) pain response. The ICV injection of histamine at doses of 25, 50 and 100 μg significantly (P < 0.05) decreased the time duration spent licking and biting the injected paw. Mepyramine and ranitidine, used alone produced no effects. The ICV pretreatments with mepyramine and ranitidine at the same dose of 200 μg significantly (P < 0.05) prevented histamine (100 μg, ICV)-induced antinociception. These results indicate that activation of brain histamine with ICV injection of exogenous histamine produces antinociception. Central histamine H1 and H2 receptors may be involved in the centrally administered histamine-induced antinociception in the formalin-induced pain in rabbits.