Cholestasis is associated with
analgesia. The
histamine H(2) receptors control pain perception. The involvement of
histamine H(2) receptors on modulation of nociception in a model of elevated endogenous
opioid tone,
cholestasis, was investigated in this study using
zolantidine and
cimetidine as two H(2) receptor antagonists and
dimaprit as a selective H(2) receptor agonist.
Cholestasis was induced by
ligation of the main bile duct using two
ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of
zolantidine (10, 20 and 40 mg/kg) and
cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while
dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of
zolantidine and
cimetidine in cholestatic rats was attenuated by co-administration of
naloxone.
Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the
histamine H(2) receptor system may be involved in the regulation of nociception during
cholestasis. According to the hypothesis that increasing the nociception threshold in
cholestasis may lead to a decrease in the perception of
pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic
pruritus.