Methadone ameliorates the effects of morphine withdrawal in rat model of physical dependence
Methadone, a synthetic opioid agonist used for opioid use disorder, has been assessed in a rat model of physical dependence. Male Sprague-Dawley rats (n=30) were handled, given vehicle (3 days) and then randomised into 2 groups receiving vehicle (po bid; n=10) or morphine (30 mg/kg po bid, n=20) for 16 days. Morphine was stopped and rats given vehicle (n=9) or methadone (20 mg/kg po bid, n=9) for 7 days. Body weight, food and water intake and a wide range of behaviours (blinded) were assessed daily. Morphine increased body weight on Day 2 followed by a decrease from Day 5 onwards. Food intake was decreased on all days (1-14) and water intake increased on Day 1 and then decreased from Day 3 onwards. Morphine produced hunched posture, Straub tail, increased body tone, increased locomotor activity, increased reaction to sound, increased irritability on dosing/gentle restraint, explosive movements, exophthalmos (bulging eyes) and stained fur. Morphine withdrawal decreased body weight, reduced food and water intake and then produced rebound hyperphagia and hyperdipsia. New behaviours and physical signs observed during withdrawal were arched back, high stepping, decreased body tone, tail rattle, piloerection, increased respiration and diarrhoea. This is clear evidence of physical dependence. Methadone significantly decreased body weight, similar to that seen upon morphine withdrawal but with greater magnitude on days 20 to 24. Methadone reduced food and water intake similar to that seen upon morphine withdrawal, but with greater magnitude on days 19 to 23. However, rebound hyperphagia and hyperdipsia was blunted when compared to the morphine withdrawal group. New behaviours and physical signs observed with methadone but not seen during morphine withdrawal included ataxia/rolling gait, stereotypy, decreased respiration, salivation, biting/licking of the cage and eating sawdust. Behaviours observed during morphine withdrawal/methadone dosing that were seen with morphine but not in morphine withdrawal phase included Straub tail, increased body tone, increased locomotor activity, increased reaction to sound, explosive movements and exophthalmos. Animals on methadone exhibit some behaviours and physical signs observed during morphine administration but which are not observed during morphine withdrawal. The withdrawal effects of morphine on food and water intake are blunted by methadone. In addition, some behaviours that disappear during morphine withdrawal are seen during methadone administration. Thus, it would appear that methadone, at least in part, decreases the withdrawal effects of morphine seen in this model.