Alpha₂-adrenoceptor and NO mediate the opioid subsensitivity in isolated tissues of cholestatic animals

1 Our previous report showed that in acute cholestasis, the subsensitivity to morphine inhibitory effect on electrical-stimulated contractions develops significantly faster in guinea-pig ileum (GPI) and in mouse vas deferens (MVD) (45.2 and 29.9 times, respectively) compared with non-cholestatic subjects. 2 The possible contribution of α₂-adrenoceptor and nitric oxide (NO) pathways on the development of tolerance was assessed in GPI and MVD of cholestatic subjects. 3 Daily administration of naltrexone (20 mg kg ^-1), yohimbine (5 mg kg^-1), and N^ω -nitro-L-arginine methyl ester (L-NAME) (3 mg kg^-1) to cholestatic animals significantly (P-value < 0.05) inhibited the process of subsensitivity in all groups. 4 Consistent with the literature, it was concluded that both the α₂-adrenergic system and NO have close interaction with the opioid system and may underlie some of the mechanisms involved in the subsensitivity development to opioids in acute cholestatic states.