Modulation of cholestasis-induced antinociception by CCK receptor agonists and antagonists

Acute cholestasis is associated with increased activity of the endogenous opioid system. Agonists and antagonists of cholecystokinin (CCK) receptors are known to modulate opioid-induced antinociception. In the present study, the effect of the CCK receptor agonist caerulein and the antagonist proglumide on antinociception induced during acute cholestasis was investigated in rats using the tail-flick test. A significant increase in nociception threshold was observed in bile duct ligated (BDL) rats compared to sham-operated controls that was maximum on day 7 after the operation and decreased thereafter. Proglumide (40 mg/kg, i.p.) did not affect nociception in unoperated and sham-operated animals, but exerted a significant potentiation of antinociception in cholestatic rats in a way similar to its potentiation effect on unoperated morphine-treated (2 mg/kg, s.c.) animals. Caerulein (0.005, 0.001, 0.01 and 0.02 mg/kg, s.c.), which did not change nociception per se or in sham-operated animals, also significantly potentiated the antinociception in BDL rats as well as in morphine-treated unoperated controls. Caerulein-induced potentiation of antinociception in BDL animals was completely reversed by proglumide pretreatment. Our findings show that, in cholestatic animals, modulation of nociception by the CCK system is different from normal subjects and resembles the state observable in morphine-administered subjects.