Antinociceptive mechanisms of dimaprit administered intrathecally in mice

Intrathecally administered dimaprit (10-40 mu g), an H-2 receptor agonist, produced a dose-dependent antinociceptive effect in mice, using the tail-fl ick test as the experimental parameter. The effect was significantly inhibi ted by pretreatment with naloxone (a nonspecific opioid receptor antagonist ), beta-funaltrexamine (a specific mu-opioid receptor antagonist) and nor-b inaltorphimine (a specific kappa-opioid receptor antagonist), but not with naltrindole (a specific delta-opioid receptor antagonist). Pretreatment wit h pertussis toxin, cholera toxin and 3-isobutyl-1-methylxanthine also inhib ited the antinociceptive effect of dimaprit. Furthermore, the antinocicepti ve effect of dimaprit was attenuated by pretreatment with nimodipine (an L- type Ca2+ channel blocker), calmidazolium (a calmodulin antagonist) and KN- 62 (a Ca2+/calmodulin-dependent protein kinase II inhibitor). These results suggest that stimulation of spinal H-2 receptors produces an antinocicepti on, which is coupled with pertussis toxin- and cholera toxin-sensitive G pr oteins and regulated by spinal mu- and kappa-opioid pathways. Furthermore; cAMP dependent phosphodiesterase, Ca2+ influx through the L-type Ca2+ chann els, binding with calmodulin and activation of Ca2+/calmodulin-dependent pr otein kinase II in the spinal cord appear to be involved in H-2 receptor-st imulated antinociception.