Effects Of Digoxin On Naloxone-precipitated Morphine Withdrawal Symptoms And Its Mechanism

Although opiates represent one class of the most effective analgesics, repeated administration of opiates results in severe physical dependence. This major side effect of opiate administration limits their clinical utility, and most importantly, contributes to opioid addiction and so causes several social problems relevant to its non-clinical use. To explore the possible mechanism and develop new methods for morphine withdrawal syndrome is urgent. The activity of Na~+/K~+-ATPase was found to be modulated by opiates both in vitro and in vivo many years ago. However, the effects of Na~-/K~+-ATPase inhibitors on naloxone-precipitated morphine withdrawal symptoms have yet to see any reports.In the present study, a comparative study of Na~-/K~+-ATPase inhibitors,digoxin and ouabain on morphine withdrawal symptoms and locomotor activity was done in mice,while another cardiotonic drug milrinone (non-inhibitor of Na~+/K~+-ATPase) served as a control study. We found that higher dose of digoxin(1.0or2.5mg/kg) inhibited dose-dependently the locomotor activity and naloxone-precipitated withdrawal syndrome such as jumps and weight loss, while lower dose of digoxin(0.1or0.25mg/kg) only inhibited withdrawal weight loss without affecting locomotor activity and naloxone-precipitated withdrawal jumps in mice. Both milrinone and ouabain inhibited weight loss, while none of them affected withdrawal jumps and locomotor activity in mice. The present study suggests that cardiotonic function and central inhibition of digoxin play an important role in the inhibition of morphine withdrawal symptoms.To further elucidate the mechanism, we evaluated the effects of the digoxin on morphine withdrawal symptoms in rats. The results demonstrated that pretreated with digoxin (0.05-0.2mg/kg) significantly reduced most withdrawal signs tested, including teeth chattering, irritability, diarrhea, weight loss and total score of withdrawal signs in rats. Also digoxin dramatically attenuated naloxone induced increase in SBP and heart rates in morphine dependent rats while did not induce significant changes in the normal physiological state of rats. Digoxin reversed the increased norepinephrine turnover during morphine withdrawal and inhibited the increase in phosphorylated ERK1/2expression induced by naloxone precipitated withdrawal in caudate putamen(CPU), prefrontal cortex(PFC), hypothalamus(Hth) and left ventricle, but not in right ventricle. We speculated that the autonomic nervous system, norepinephrine neurotransmitter systems and ERK signal transduction system were involved in this process.