Background and purpose: Histamine is a neurotransmitter present in the brain of mammals which produces its physiological effects on target cells by stimulation of three types of receptors H1, H2 and H3.Various reports nowadays indicate the role of histamine in reduction of pain transmission. This study was designed to determine the role of histamine receptors in reduction of pain.Materials and Methods: In this study, effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by thermal (hot plate) and chemical (acetic acid-induced abdominal writhing) stimuli.Results: Intracerebroventricular (I.C.V.) injection of the histamine H1 receptor agonist HTMT (50 µ g per mouse) produced a significant hypernociceptive response in the hot plate and writhing tests.This dose of HTMT had no significant effect on the motor coordination on rota rod test.Intra peritoneal (I.P) injection of histamine H1 receptor antagonist, dexchloropheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) caused a dose dependent antinociception in both tests. But since all the doses of dephenhydramine in this experiment caused motor impairment in rota rod, it seems that diphenhydramine is not a real pain antagonist.Combined injection of HTMT with dexchlorpheniramine (20 mg/kh, i.p) did not change pain threshold in hot plate teat. The histamine H2 receptor agonist, dimaprit (50 and 100 µ gm per mouse, I.C.V) and ranitidine, histamine H2 receptor antagonist (50 and 100 µ gm per mouse, I.C.V) raised the pain threshold in both hot plate and writhing tests. Histamine H2 receptor agonist, imetit (25-50 mg/kg, I.P.) and histamine H3 receptor antagonist, thioperamide (25 and 50 mg/kg, I.P.) decreased or increased pain threshold in hot plate, respectively.The dose of 25 mg/kg, I.P. of thioperamide significantly antagonized hyper nociceptive response induced by imetit.Conclusion: These results suggest that histamine receptor mechanisms have a retrogative effect on the pain caused by hot plate.