Intrathecal coadministration of clonidine with serotonin receptor agonists produces supra-additive visceral antinociception in the rat.

The intrathecal (i.t.) coadministration of sub-antinociceptive doses of clonidine, an alpha 2-adrenoceptor agonist, with DOI or RU-24969 (5-HT2 or 5-HT1B receptor agonists, respectively) produced dose-dependent supra-additive antinociceptive effects in a model of visceral pain. The enhanced attenuation of responses to noxious colorectal distension produced by the coadministration of these drugs is evidenced by significant leftward shifts in the dose-response curves as compared to those of each drug alone and by isobolographic analysis. The supra-additive antinociceptive effects produced following the i.t. coadministration of clonidine with RU-24969 were antagonized by i.t. pretreatment with phentolamine; the coadministration of phentolamine with methysergide produced no greater antagonism of effects. The supra-additive antinociceptive effects produced by i.t. coadministration of clonidine with DOI were antagonized by i.t. pretreatment with methysergide; the coadministration of methysergide with yohimbine produced no greater antagonism of effects. These data suggest that receptors acted upon by descending bulbospinal neurons interact to modulate the rostrad transmission of visceral nociceptive transmission.