Until recently the only description of an opiate abstinence syndrome in neonates was for human infants. Yet the complexities of the human setting make it impossible to tease apart the aspects of withdrawal that are due to opiate use, and those that are due to the abuse of other drugs, poor prenatal care, under-nutrition, or any of the myriad of other complications experienced by the mothers of these children. Three groups, including ours, have detailed an opiate withdrawal syndrome in the infant rat. The withdrawal syndrome slowly changes over development to reach, around puberty, the classic constellation of withdrawal behaviors so often described for the adult animal. There are both similarities and differences in the neural substrates underlying withdrawal in infants and adult. Although the neural structures mediating withdrawal behaviors are similar, there are important differences in the role of NMDA receptors mediating these behaviors. NMDA blockers have no effect, or worsen, withdrawal at 7 days of age but ameliorate it at 21 days of age. In contrast, nitric oxide synthase (NOS) inhibitors block withdrawal throughout development. Thus at young ages, NMDA receptors and NOS differentially regulate precipitated withdrawal. Because the abstinence syndrome in the infant is now described in great detail, we are poised to ask a number of questions that could not have been addressed before. In particular little is known of the genetic changes induced by opiate dependence and withdrawal in the adult animal, and nothing is known in the infant. The experiments proposed here define changes in gene expression induced by opiate withdrawal at different stages of development. We test morphine withdrawal at 7 and 21 days of age with and without NMDA blockers and NOS inhibitors to assess specific changes in patterns of gene expression under conditions where withdrawal is or is not expressed. We use gene microarray technology to assess specific changes in patterns of gene expression and advanced bioinformatic methods to analyze and provide access to these data. In each case we assay specific regions of the CNS involved in withdrawal, including the periaqueductal gray of the midbrain, the locus ceruleus, amygdala, nucleus accumbens and spinal cord. By assessing simultaneous changes in expression levels of large numbers of genes, we can identify the nature of the biological responses of specific brain regions to opiate withdrawal. In turn, these data allow a more complete understanding of the mechanisms underlying the differences in drug response between infants and adults, and provide a detailed picture of the developmental changes in patterns of gene expression linked to severity of opiate withdrawal. These results can then direct the development of novel treatments for the opiate withdrawal syndrome in this population of at risk infants.
