ANTINOCICEPTIVE MECHANISMS OF BETAHISTINE ADMINISTERED INTRATHECALLY IN MICE

To investigate the role of spinal H-1-receptors in spinal antinocicept ive mechanisms, the antinociceptive effect of betahistine, a H-1 recep tor agonist, were determined using the tail-flick test in mice. Betahi stine (100-400 mu g) produced dose-dependently an antinociception and its maximal effect was exerted at 5 min after betahistine administrati on. The antinociceptive effect of betahistine (400 mu g) was dose-depe ndently blocked by i.t. pretreatment with naloxone (a nonspecific opio id receptor antagonist; 0.1-2.0 mu g), beta-funaltrexamine (a specific mu-opioid receptor antagonist; 10-100 ng), naltrindole (a specific mu -opioid receptor antagonist; 10-20 mu g), and nor-binaltorphimine (a s pecific kappa-opioid receptor antagonist; 10-20 mu g). Furthermore, i. t, pretreatment of mice with cholera toxin (0.5 mu g), pertussis toxin (0.5 mu g) or 3-isobutyl-1-methylxanthine (a cAMP dependent phosphodi esterase inhibitor; 0.5-1.0 mu g) attenuated significantly the betahis tine-induced antinociception. I.t. pretreatment of mice with nimodipin e (an L-type Ca2+ channel blocker; 5-10 ng), calmidazolium (a calmodul in antagonist, 1 - 10 ng) or KN-62 (a Ca(2+/)calmodulin-dependent prot ein kinase II inhibitor; 1-10 ng) also attenuated significantly the be tahistine-induced antinociceptive effect. These results suggest that s timulation of spinal H-1 receptors produces an antinociception, which is regulated by spial opioid pathways and the coupling with the pertus sis and cholera toxin-sensitive G proteins is necessary. Furthermore, cAMP dependent phosphodiesterase, Ca2+ influx through the L-type Ca2channels, binding with calmodulin and activation of Ca2+/calmodulin-de pendent protein kinase II in the spinal cord appear to be involved in H-1 receptor-stimulated antinociception.