EFFECTS OF KETAMINE AND MIDAZOLAM ON MORPHINE INDUCED DEPENDENCE AND TOLERANCE IN MICE

The aim of this study was to investigate the effects of ketamine and midazolam on prevention of the development of morphine tolerance and dependence in mice. Different groups of mice received morphine (50 mg/kg, sc), morphine (50 mg/kg, sc) + ketamine (25,50,75 mg/kg, ip), morphine (50 mg/kg, sc) + midazolam (0.5,1,2 mg/kg, ip) , morphine (50 mg/kg , sc) + ketamine (50 mg/kg, ip) + midazolam (1 mg/kg, ip) once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg, ip) on fifth day. Withdrawal symptoms were assessed by administration of naloxane (4 mg/kg, ip) two hours after co-administration of morphine with either ketamine or midazolam. It was found that pretreatment with ketamine or midazolam decreased the degree of tolerance and withdrawal symptoms. Additionally co-administration of ketamine and midazolam before morphine therapy decreased the tolerance and dependence significantly. From these results it may concluded that administration of ketamine and midazolam alone or in combination could prevent the development of tolerance and dependence to morphine. These effects can be related to the N-Methyl-D-Aspartate (NMDA) receptor antagonist behavior of ketamine and GABA-receptor agonist behavior of midazolam.

[1]  C. Vergin,et al.  Ketamine and midazolam for invasive procedures in children with malignancy: a comparison of routes of intravenous, oral, and rectal administration. , 2004, Journal of tropical pediatrics.

[2]  H. Ding,et al.  Pretreatment with midazolam suppresses morphine withdrawal response in mice and rats. , 2002, Acta pharmacologica Sinica.

[3]  K. Anand,et al.  Protein kinases modulate the cellular adaptations associated with opioid tolerance and dependence , 2001, Brain Research Reviews.

[4]  S. Mercadante,et al.  Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. , 2000, Journal of pain and symptom management.

[5]  K. A. Trujillo.  Are NMDA receptors involved in opiate-induced neural and behavioral plasticity? , 2000, Psychopharmacology.

[6]  J. Delfs,et al.  Presynaptic Inhibition of GABAB-Mediated Synaptic Potentials in the Ventral Tegmental Area during Morphine Withdrawal , 1999, The Journal of Neuroscience.

[7]  G. Guilbaud,et al.  The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy , 1998, British journal of pharmacology.

[8]  G. Aghajanian,et al.  Molecular and cellular basis of addiction. , 1997, Science.

[9]  S. Tokuyama,et al.  Direct evidence for a role of glutamate in the expression of the opioid withdrawal syndrome. , 1996, European journal of pharmacology.

[10]  K. Elliott,et al.  N-Methyl-D-Aspartate (NMDA) Receptors, Mu and Kappa Opioid Tolerance, and Perspectives on New Analgesic Drug Development , 1995, Neuropsychopharmacology.

[11]  I. Lorenz,et al.  Effect of the NMDA‐antagonist, MK 801, on benzodiazepine‐opioid interactions at the spinal and supraspinal level in rats , 1995, British journal of pharmacology.

[12]  John T. Williams,et al.  Dopamine D1 receptors facilitate transmitter release , 1993, Nature.

[13]  N. Mercuri,et al.  5-hydroxytryptamine1B receptors block the GABAB synaptic potential in rat dopamine neurons , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  R. North,et al.  Opioids excite dopamine neurons by hyperpolarization of local interneurons , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  K. Gysling,et al.  Morphine-induced activation of A10 dopamine neurons in the rat , 1983, Brain Research.

[16]  C. Chin,et al.  STUDY THE EFFECT AND MECHANISM OF DEXTROMETHORPHAN ON PREVENTING THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE IN RATS , 2002 .