The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by spinally administered morphine, beta-endorphin and U50, 488H. The effects of intrathecal (i.t.) injections with cyproheptadine (a histamine-1 (H1) receptor antagonist), ranitidine (an H2 receptor antagonist), or thioperamide (an H3 receptor antagonist) injected i.t., on the antinociception induced by morphine, beta-endorphin or trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide (U50, 488H) injected intrathecally (i.t.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (20 micrograms), ranitidine (20 micrograms), or thioperamide (20 micrograms) alone did not produce any antinociceptive effect. i.t. pretreatment with cyproheptadine attenuated the inhibition of the tail-flick response induced by i.t. administered morphine or beta-endorphin, but not U50, 488H. In addition, i.t. pretreatment with ranitidine attenuated the inhibition of the tail-flick response induced by i.t. administered morphine, beta-endorphin, or U50, 488H. Furthermore, the i.t. pretreatment with thioperamide attenuated the inhibition of the tail-flick response induced by beta-endorphin or U50, 488H, but not morphine, administered i.t. Our results indicate that spinal H1 receptors may be involved in the production of antinociception induced by spinally applied morphine or beta-endorphin- but not U50, 488H. Spinal H2 receptors appear to be involved in spinally administered morphine-, beta-endorphin- and U50, 488H-induced antinociception. Supraspinal histamine H3 receptors may be involved in the production of antinociception induced by supraspinally applied beta-endorphin or U50, 488H, but not morphine.