Moclobemide is an antidepressant which affects the monoaminergic neurotransmitter system through a reversible inhibition of monoamine oxidase (MAO), preferentially type A. We examined the antinociceptive effects of moclobemide alone and in conjunction with specific opioid, adrenergic and serotonergic antagonists, using the mouse-tail flick test. Intraperitoneal moclobemide produced a dose-dependent antinociceptive effect with an ED50 of 69.1 mg/kg. Tests with selective antagonists yielded positive results only for yohimbine (P < 0.001), implying a noradrenergic mechanism of action in the moclobemide antinociceptive effect. This was confirmed by the coadministration of moclobemide with inactive doses of prototype agonists of the opioid, adrenergic and serotonergic systems. Only clonidine, an alpha2 agonist, significantly shifted (8-fold) the dose response curve of moclobemide. We conclude that there is a selective involvement of the alpha2 adrenergic pathways in the moclobemide-induced antinociceptive effect and a lesser involvement (if any) of the opioid, serotonergic and alpha1 adrenergic mechanisms. More research is needed to establish a possible role for moclobemide in pain management.