INBRE

Neonatal intensive care exposes preterm neonates to repetitive pain, stress, and maternal separation. Preterm neonates are exposed to acute and inflammatory pain caused by frequent heelsticks, localized infections, and various other invasive procedures. Previous experiments showed that repetitive pain in neonatal rat pups causes increases in neuronal cell death, subsequently associated with poor cognitive performance and abnormal behaviors during adulthood. Use of NMDA receptor antagonists prevented neuronal cell death and diminished some of the long-term behavioral effects of repetitive inflammatory pain in newborn rats. Ongoing experiments designed to examine the cellular and molecular mechanisms of pain-induced neuronal cell death suggest that apoptosis does not play a major role. Candidate genes activated by excitotoxic damage to immature neurons were screened using cDNA microarray analysis. We will build on these preliminary data to define the mechanisms regulating neuronal cell death following neonatal pain. In order to control for variable gene expression during rapid brain development in this age group, additional cDNA microarray studies will compare gene expression between pooled RNA samples from undisturbed control rats with individual samples from experimental rats. Areas examined will include the somatosensory cortex and other cortical areas, hippocampus and limbic system areas, thalamus and hypothalamus. Genes showing >2.5-fold expression differences will be characterized by RT-PCR and Northern blotting, mostly selecting the genes that regulate neuronal cell survival and differentiation. Promising candidate genes include transthyretin, interleukin enhancer binding factor 3 (Ilf3), and Smad 5. These studies will be repeated after applying repetitive neonatal pain paradigm at different developmental periods (e.g. P1-P4, P6-P9, P11-P14) and preceded by specific analgesic agents (e.g. Ketamine, Morphine, Clonidine). We will confirm these changes in gene expression with future studies of protein expression, using Western immunoblotting and immunohistochemistry techniques, where specific antibodies are available. These data will identify alternative therapeutic approaches that can prevent or limit the long-term behavioral and cognitive sequelae resulting from repetitive neonatal pain.

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Updated 10/31/2005

The Arkansas INBRE is Supported by a grant from the National Institutes of Health
and the National Center for Research Resources (P20 RR-16460).

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