Mechanisms of opiate tolerance and dependence in the rat

Drug addiction is a complex phenomenon with various biological, psychological and social causes and consequences, which belongs to the major problems of today's society. Opiates have been used and misused for thousand of years and addiction to them develops both in humans and in animals. The mechanisms behind this phenomenon are not fully understood. We examined the roles of the neuropeptide cholecystokinin (CCK) and the N-methyl-D-aspartate (NMDA) receptor for glutamate, two of the most important anti-opioid neurotransmitter systems, in the development of morphine tolerance.

An antagonist of CCK-B receptors acutely partially reversed established morphine tolerance, indicating a role for CCK through activation of CCK-B receptors in maintaining morphine tolerance. The role of the NMDA receptor in the development of morphine tolerance was not so clear, because NMDA antagonists of different types significantly potentiated morphine analgesia both in drug naive and morphine tolerant rats. The combination of a CCK-B antagonist and NMDA antagonist did not potentiate each other.

We also examined the role of genetic differences in opiate sensitivity and the development of tolerance among four rat strains: Sprague-Dawley, Spontaneously Hypertensive, Wistar-Kyoto and Dark Agouti. Significant differences in sensitivity to nociceptive stimulation, response to morphine, morphine tolerance and withdrawal and in opioid-NMDA receptor interactions was observed among the different strains of rats, some of which may be of genetic origin. Both gender and strain differences in codeine metabolism were observed. Female rats did not form norcodeine via N-demethylation in any of the four strains. Both male and female Dark Agouti rats showed deficits in the formation of morphine via O-demethylation of codeine as a result of reduced CYP2D1 enzyme activity.

These results may reflect genetic differences also observed in humans in opiate responsiveness and pain sensitivity, which could be related to genetic differences in drug metabolism, as well as differences in levels of endogenous opioids.