Possible involvement of the opioidergic system in the modulation of body temperature, jumping behavior and memory process in cholestatic and addicted mice

Cholestasis is related to an increased plasma level of endogenous opioid levels. Naloxone-induced withdrawal syndrome has been reported in a mouse model of cholestasis. Moreover, studies revealed that the memory process is affected by cholestasis. Thus, we aimed at determining whether pharmacological manipulation of the opioidergic system is involved in signs of cholestasis disease such as hypothermia and withdrawal behaviors such as jumping behavior as well as memory process in mice. Cholestasis was induced by bile duct resection in mice and physical dependence was induced by administration of morphine and/or tramadol three times daily (8, 12 and 16 h) at the doses of 25, 50 and 75 mg/kg during three consecutive days. The memory process was assessed by a step-down passive avoidance test. Our results indicated that cholestatic mice showed hypothermia whereas cholestatic- and drug dependent mice indicated hyperthermia. Moreover, administration of morphine (50 mg/kg) and/or tramadol (50 mg/kg) on the 4th day, 2 h before naloxone injection significantly decreased latency to first jumping but increased the number of jumping and rearing behavior as well as locomotor activity in BDL-vs. sham-operated mice. In addition, the latency time of the step-down test decreased in BDL-vs. sham-operated group, showing impairment of memory in BDL mice. The results of this study support the evidence that (1) the opioidergic system involved in thermoregulation of cholestasis mice, (2) μ-opioid receptors play an important role in withdrawal behaviors, and (3) memory process is affected by cholestasis and addiction in mice.