Modulation of social and depression behaviors in cholestatic and drug-dependent mice: possible role of opioid receptors.

Objectives: Social behavior, a set of motivating activities critical for survival, is disturbed in cholestasis conditions and many substance abusers as well as psychiatric disorders. The documented loss of social interest in cholestatic patients may be associated with depressive symptoms. Interestingly, the endogenous opioid system is involved in the modulation of depression. Methods in this research: , we assessed the effect of cholestasis and drug dependence on social and depression behaviors using the Three-Chamber Paradigm Test, Forced Swim Test (FST), and Tail Suspension Test (TST) as well as Open Field Test (OFT) in male NMRI mice. Results: The results indicated that alone administration of morphine and tramadol, as well as co-administration of them, increased social motivation and novelty but decreased depression in bile duct ligated mice. Whereas, alone administration of naloxone (a µ-opioid receptor antagonist) and co-administration of it along with morphine and tramadol decreased social motivation and novelty while enhanced depression in the sham-operated and bile duct ligated mice. These administrations of drugs did not change locomotor activity compared to the control group. Conclusion: In conclusion, it appears that (i) both cholestasis and drug dependence impaired social motivation behavior, as well as induced depression-like behavior in the bile duct, ligated mice, (ii) alone administration of morphine and tramadol as well as co-treatment of them may protect against cholestasis and drug dependence induced abnormal behaviors, (iii) µ-opioid receptors play an important role in modulation of social motivation and depression behaviors in mice.

Enhanced anxiolytic and analgesic effectiveness or a better safety profile of morphine and tramadol combination in cholestatic and addicted mice.

The involvement of the opioidergic system on anxiolytic and antinociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligation (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency, which was reversed by naloxone. Coadministration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (a) cholestasis and addiction affect anxiety and pain behaviors, (b) µ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, and (c) cotreatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.

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.