The human infant is often exposed to opiate drugs over extended periods of time, either due to drug abuse of the mother or because of medical conditions. Two serious clinical problems are the development of tolerance to the medical use of opiates for analgesia and dependence to both prescribed and abused opiates. Little is known of the mechanisms that mediate either withdrawal or tolerance in the infant in large part because appropriate animal models have only recently been developed. Although many of the biological mediators of opiate withdrawal in the infant are similar to those of the adult, we have recently discovered that NMDA glutamate antagonists, which are effective antidotes for withdrawal and tolerance to opiates in the adult, are fully ineffective in the infant rat and may indeed exacerbate both withdrawal and tolerance in the young. In contrast, our preliminary data show that both an AMPA glutamate receptor blocker and a metabotropic glutamate receptor (mGluR) agonist completely prevent the expression of morphine withdrawal. We hypothesize specific developmental mechanisms that could explain these data including developmental differences in glutamate receptor subtypes and subunits and alterations in the ability of opiates to up- and downregulate glutamate receptors. The experiments described in this application provide detailed descriptions of the effects of NMDA, AMPA and mGlu receptor antagonists and mGluR Group H agonists on precipitated withdrawal and tolerance to the analgesic effects of morphine both in vivo, measured behaviorally or by c-fos expression, and measured electrophysiologically in the isolated spinal cord preparation. The latter preparation allows us to focus experiments in subsequent aims on the spinal cord and to describe both the normal maturation of glutamate receptors and the ability of morphine to up- or downregulate those receptors. In the final aim, we study mice with genetic disruptions of the normal expression of specific glutamate receptors to determine if the changes in withdrawal and tolerance in the infant mice follow the predictions based on the hypotheses put forth and the pharmacological and biochemical data from the prior aims. The results of these experiments will provide substantial information about mechanisms by which glutamate receptor function is different in the infant than the adult and provide direction for the development of pharmacological tools that are uniquely effective in the human infant.
Showing the most recent 10 out of 23 publications
