The effect of the serotonergic system on opioid withdrawal-like syndrome in a mouse model of cholestasis.

There is a marked elevation of endogenous opioid levels in plasma of human subjects with biliary cirrhosis as well as animal model of cholestasis. In addition, development of morphine tolerance and dependence has been shown to be inhibited by drugs which reduce brain serotonin levels. However, intracerebroventricular injection of serotonin increases the morphine analgesia. In the present study we have investigated the role of the serotonergic pathway in determining the withdrawal syndrome in a mouse model of cholestasis. There were three experimental groups: unoperated mice, sham operated mice and mice in which the main bile duct was ligated. Physical dependency was assessed by precipitating a withdrawal syndrome (writing, climbing, rearing, grooming and jumping) by naloxone (2 mg/kg) 5 days after induction of cholestasis. In separate experimental same groups, the antinociception was evaluated by the tail flick latency (TFL) test. Administration of serotonin receptors antagonists, cyproheptadine (10 mg/kg), methysergide (6 mg/kg) and ondansetron (10 mg/kg) attenuated withdrawal signs and decreased the antinociception. However, treatment by fluoxetine (15 mg/kg), an inhibitor of serotonin reuptake, increased the withdrawal signs and antinociception. These experiments lead us to conclude that the naloxone-precipitated withdrawal signs which occur in the mouse model of cholestasis are potentially dependent on the serotonergic pathway. Copyright 2000 John Wiley & Sons, Ltd.

Endogenous nitric oxide modulates naloxone-precipitated withdrawal signs in a mouse model with acute cholestasis.

Cholestasis liver disease is associated with clinical and experimental findings consistent with increased opioidergic neuromodulation, increased plasma total activity, and elevated plasma enkephalin concentrations. The effect of the nitric oxide (NO) synthase inhibitor, L-nitro-arginine (L-NA, 0.03, 0.1, 0.3, 1 mg/kg), and the nitric oxide precursor, L-Arg (30 mg/kg), on antinociception induced by bile duct resection or sham operation, as well as on opioid dependence, was examined in male albino Swiss mice. Repeated (5 days) administration of L-NA attenuated signs of dependence, as assessed by naloxone (5 mg/kg)-precipitated withdrawal, and decreased the antinociception; however, L-Arg potentiated withdrawal signs and increased the antinociception. The results of this study support the involvement of the L-arginine/nitric oxide pathway in the opioidergic-dependent manifestation of cholestasis in an animal model.

Inhibition by L-NA, a nitric oxide synthase inhibitor, of naloxone-precipitated withdrawal signs in a mouse model of cholestasis.

Following the naloxone administration in bile duct resected animals, striking opioid withdrawal signs are observed due to increased opioidergic tone. Pretreatment of animals with L-nitro arginine, a nitric oxide synthase inhibitor, reduces the naloxone-precipitated withdrawal signs as well as increase the antinociception. The results of this study support evidence for the involvement of the L-arg-nitric oxide pathway in opioidergic-dependent manifestation of cholestasis in an animal model.