u-50488 and Cholestasis

Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-2 Receptor Agonists; Animals; Antipruritics; Bile Ducts; Cholestasis; Clonidine; Disease Models, Animal; Ligation; Liver; Male; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Pruritus; Receptors, Opioid, kappa

The rate and degree of subsensitivity development to morphine (mu-opioid receptor, preferred, but not selective agonist) and U50488H (highly selective kappa-opioid receptor agonist) were assessed in vitro on guinea pig ileum (GPI) of cholestatic animals 2, 5, and 7 days after bile duct ligation. In addition to this phenomenon of morphine, the effects of U50488H and SNC 80 (highly selective delta-opioid receptor agonist) were studied in vitro on mice vas deferens (MVD) of cholestatic animals 2, 5, 7, 10, and 15 days after bile duct ligation. The IC(50) for each compound was determined in these preparations. The ratio of the IC(50) in bile duct-ligated animals to sham and control animals provides a quantitative index for the degree of subsensitivity development to each agonist. For any given time, the highest degree of subsensitivity to morphine was observed in GPI of cholestatic animals, whereas in MVD obtained from the cholestatic animals, the highest degree of subsensitivity developed to inhibitory effect of SNC 80. The subsensitivity development in cholestatic animals was time dependent; in GPI the maximum subsensitivity developed after 7 days of the operation, whereas the maximum subsensitivity in MVD developed 15 days after bile duct ligation. Moreover, subsensitivity to exogenous acetylcholine and norepinephrine in GPI and MVD, respectively, did not develop in the presence of subsensitivity to opioids in cholestatic animals. Significant accumulation of endogenous opioids in plasma of cholestatic animals has been shown in several studies and this may account for a significant development of subsensitivity to inhibitory effects of opioid agonists.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzamides; Cholestasis; Dose-Response Relationship, Drug; Guinea Pigs; Ileum; In Vitro Techniques; Male; Mice; Morphine; Muscle Contraction; Narcotics; Piperazines; Receptors, Opioid; Time Factors; Vas Deferens