A comparison of the effects of digoxin, ouabain and milrinone on naloxone-precipitated withdrawal syndrome in mice

• Published in: European journal of pharmacology Vol. 694; no. 1-3; pp. 69 - 74
• Main Authors: Bai, Yin-Liang, Chu, Qin-Jun, Li, Jing, Chen, Yong-Yan, Li, Wen-Jie, Zhang, Qi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.11.2012
• Subjects: Animals; blood-brain barrier; Cardiotonic Agents - administration & dosage; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Digoxin; Digoxin - administration & dosage; Digoxin - pharmacology; Digoxin - therapeutic use; dose response; Female; jumping; locomotion; Locomotor; Male; Mice; Milrinone; Milrinone - administration & dosage; Milrinone - pharmacology; Milrinone - therapeutic use; Morphine; Morphine - pharmacology; Motor Activity - drug effects; naloxone; Naloxone - pharmacology; Ouabain; Ouabain - administration & dosage; Ouabain - pharmacology; Ouabain - therapeutic use; sodium; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - etiology; Substance Withdrawal Syndrome - physiopathology; weight loss; Weight Loss - drug effects; Withdrawal syndrome; Morphine; Milrinone; Digoxin; Withdrawal syndrome; Locomotor; Ouabain
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2012.08.004

Modulation of Na+, K+-ATPase activity by acute and chronic opiates has been established for many years. However, the effects of digoxin, a putative inhibitor of Na+, K+-ATPase, on naloxone-precipitated morphine withdrawal syndrome are unknown. In the present study, a digoxin dose-response curve was conducted to observe the effects on naloxone-precipitated withdrawal and locomotor activity in mice. Higher doses of digoxin (1.0 and 2.5mg/kg) inhibited locomotor activity and naloxone-precipitated withdrawal jumping and weight loss, while lower doses of digoxin (0.1 and 0.25mg/kg) inhibited withdrawal weight loss precipitated by naloxone without affecting locomotor activity and naloxone-precipitated withdrawal jumping. To explore the possible mechanisms underlying this behavior, another Na+, K+-ATPase inhibitor ouabain, which does not cross the blood brain barrier, and another cardiotonic drug milrinone, a non-inhibitor of Na+, K+-ATPase, were also included in the present study. Both milrinone and ouabain inhibited, in a dose-dependent manner, naloxone-precipitated weight loss while neither affected naloxone-precipitated withdrawal jumping nor locomotor activity in mice. These results indicate that both the cardiotonic effects and central inhibition of Na+, K+-ATPase contribute to the inhibitory effects of digoxin on morphine withdrawal syndrome in mice.