Attenuation of morphine tolerance and withdrawal syndrome by coadministration of nalbuphine
Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, κ-agonist may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10∶1) significantly attenuated the development of dependence on morphine. The elevation of [3H]MK-801 binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.
Key wordsMorphine Nalbuphine Tolerance μ receptor κ receptor Autoradiography
- Di Chiara, G. and Imperato, A., Oposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.J. Pharmacol. Exp. Ther., 244, 1076–1080 (1988).Google Scholar
- Dickenson, A. H., Neurotransmitters, Drugs and Disease, in Webster R. A. and Jordan, C. C. (Ed), Blackwell Scientific Publications, Oxford, p265 (1989).Google Scholar
- Franklin, K. B. J. and Paxinos, G., The mouse brain in stereotaxic coordinates, Academic Press, San Diego, CA (1997).Google Scholar
- Narita, M., Opioid-regulated pharmacological interaction and intracellular signaling mechanism. Dissertation for Ph.D., Hoshi University, Tokyo, Japan, (1992).Google Scholar
- Picker, M. J., Yarbrough, J., Hughes, C. E., Smith, M. A., Morgan, D., and Dykstra, L. A., Agonist and antagonist effect of mixed action opioids in the pigeon drug discrimininant procedure: influence of training dose, intrinsic efficacy and interanimal differences.J. Pharmacol. Exp. Ther., 266, 756–767 (1993).PubMedGoogle Scholar