Effects of histamine receptor antagonists injected intrathecally on antinociception induced by opioids administered intracerebroventricularly in the mouse.

The present study was designed to investigate the modulatory effects of blockade of spinal histamine receptors on antinociception induced by supraspinally administered mu-epsilon-, delta-, and kappa-opioid receptor agonists. The effects of intrathecal (i.t.) injections with cyproheptadine [a histamine-1 (H1) receptor antagonist], ranitidine (a H2 receptor antagonist), or thioperamide (a H3 receptor antagonist) injected i.t., on the antinociception induced by morphine (a mu-receptor antagonist), beta-endorphin (an epsilon-receptor agonist), D-Pen(2,5)-enkephalin (DPDPE, a delta-receptor agonist) or trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohxyl] benzeocetamide (U50,488H, a kappa-receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. The antinociception was assayed using the tail-flick test. The i.t. injection of cyproheptadine (from 0.31 to 62 nmole), ranitidine (from 0.28 to 56 nmole), or thioperamide (from 0.24 to 48 nmole) alone did not show any antinociceptive effect. The i.t. pretreatment with cyproheptadine or thioperamide dose-dependently attenuated the inhibition of the tail-flick response induced by i.c.v. administered morphine (0.6 nmole), b-endorphin (0.03 nmole), DPDPE (1.5 nmole), and U50,488H (130 nmole). In addition, the i.t. pretreatment with ranitidine dose-dependently attenuated the inhibition of the tail-flick response induced by morphine, b-endorphin and U50,488H without affecting DPDPE-induced response. Our results suggest that spinal histamine H1 and H3 receptors may involved in the production of antinociception induced by supraspinally applied morphine, b-endorphin, DPDPE and U50,488H. Spinal H2 receptors appear to be involved in supraspinally administered morphine, b-endorphin- and U50,488H-induced antinociception but not DPDPE-induced antinociception.