The effect of clonidine on the antinociceptive effect of methylxanthine/baclofen and dopamine antagonist/baclofen combinations was examined to determine if alterations in noradrenaline turnover might mediate the potentiating effect of these agents. Clonidine alone had intrinsic activity in the tail flick test, so a dose and treatment schedule which produced a plateau effect was chosen. Clonidine pretreatment did not significantly alter the effect of baclofen alone, but reversed the potentiation of the action of baclofen produced by both theophylline and isobutylmethylxanthine. The intrinsic effect of isobutylmethylxanthine also was reversed. Combinations of dopamine antagonists and baclofen were potentiated or unaffected by clonidine. A possible interpretation of these results is that mutual interactions by baclofen and methylxanthines with descending noradrenergic pathways mediate the methylxanthine-induced potentiation of the antinociceptive effect of baclofen. A more specific determination of noradrenergic pathways involved in the action of baclofen will require the use of more specific alternative approaches.