Normal respiratory control in newborns, as in adults, is dependent upon neurotransmitter mediated interactions among networks of neurons comprising the brainstem respiratory centers. However, newborns are particularly prone to develop unstable respiratory patterns, suggesting important differences from adults in these interactions during the postnatal period. The long-range goal of this laboratory is to characterize excitatory and inhibitory central neuronal mechanisms which control autonomic nervous function, including respiratory drive, during the newborn period. The major objective of the present study is to characterize the effect of chronic prenatal hypoxia as a long-acting teratogen affecting inhibitory for transmitter metabolism, release and receptors. Opioid transmitters, including beta-endorphin and enkephalin, are associated with inhibition of respiratory drive, particularly in response to acute and severe hypoxia and other stresses. The present studies are to be performed in developing rats and include: 1) Identifying normal developmentally regulated mechanisms which affect availability of this class of transmitter for secretion. We will focus on glycosylation as a newly recognized mechanism regulating bioavailability of the peptides through regulation of post-translation processing of precursor peptide(s). 2) Determining the effect of prenatal hypoxemia on gene expression of the opioid precursors proopiomelanocortin and preproenkephalin, post-translation processing these precursor polypeptides, and creation of transiently increased bioactive beta-endorphin and enkephalin levels. And, 3) Characterizing the effects of prenatal maternal hypoxemia on long term regulation of opioid receptors in the newborn pup brainstem and specifically in neurons of the chemosensory pathway. Regular progression through defined developmental stages is crucial for normal development of the respiratory control system. Disruption of the normal developmental pattern due to an abnormal condition (e.g. hypoxia) during the perinatal period can lead to protracted system dysfunction possibly resulting in life threatening pathologies including apnea in premature infants, infantile apnea common in older infants, and Sudden Infant Death Syndrome.
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