The purpose of this proposal is to study the role of endorphins in ventilatory and cardiovascular control at rest and during stress (e.g. hypoxia) as a function of age and state of consciousness in unanesthetized chronically instrumented puppies and adult dogs. On the basis of our previous work, we hypothesize that various opiate receptor subtypes have different roles in cardiorespiratory control and that these roles depend on age in early life. We intend to 1) study the role of delta-, mu- and Kappa-receptors in cardiorespiratory function with maturation and 2) study the cardiorespiratory responses to moderate and severe hypoxia and determine whether these responses are mediated by the opiate receptor subtypes under consideration. Because it has been shown that morphine-like substances are enzymatic digests of B-casein, we will study the relation of milk intake to changes in plasma B-casomorphin and morphiceptin. We will measure ventilation by the barometric method, heart rate and heart rate variability using an accurate pre-processor, cardiac output using the Fick principle and 02 consumption in a closed system in puppies and dogs. Sleep will be staged using EEG, EOG and behavioral criteria. Chronic cannulae, implanted over the cisterna magna or in cerebral ventricles, will be used for sampling CSF or for injection of agonists or antagonists. Total CSF opiates will be assayed during normoxia and hypoxia and plasma and CSF morphiceptin and B-casomorphin levels will be measured after milk intake using radioimmunoassays. Autoradiographic techniques will localize receptor-agonist interaction. We believe that it is only with an understanding of the biochemical basis of defects such as hypoventilation, apnea and cardiovascular instability in the young during wakefulness and sleep that it is possible to develop new approaches to treatment of a variety of pediatric illnesses including apnea of prematurity and upper airway obstruction. This proposal is particularly relevant to the understanding of the pathogenesis of Sudden Infant Death Syndrome since this proposal is very likely to generate new and important data regarding the relation of the state of consciousness, cardiorespiratory control and 02 consumption to blood and CSF endorphin levels after milk feeding.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD015736-04A1
Application #
3313211
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1981-07-01
Project End
1989-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Marks, J D; Friedman, J E; Haddad, G G (1996) Vulnerability of CA1 neurons to glutamate is developmentally regulated. Brain Res Dev Brain Res 97:194-206
Bevensee, M O; Cummins, T R; Haddad, G G et al. (1996) pH regulation in single CA1 neurons acutely isolated from the hippocampi of immature and mature rats. J Physiol 494 ( Pt 2):315-28
Xia, Y; Warshaw, J B; Haddad, G G (1995) Chronic hypoxia causes opposite effects on glucose transporter 1 mRNA in mature versus immature rat brain. Brain Res 675:224-30
Krishnan, S N; Desai, T; Ward, D C et al. (1995) Isolation and chromosomal localization of a human ATP-regulated potassium channel. Hum Genet 96:155-60
O'Reilly, J P; Jiang, C; Haddad, G G (1995) Major differences in response to graded hypoxia between hypoglossal and neocortical neurons. Brain Res 683:179-86
Krishnan, S N; Haddad, G G (1995) Cloning of glucose transporter-3 (GLUT3) cDNA from rat brain. Life Sci 56:1193-7
Friedman, J E; Haddad, G G (1994) Anoxia induces an increase in intracellular sodium in rat central neurons in vitro. Brain Res 663:329-34
Haddad, G G; Jiang, C (1994) Mechanisms of neuronal survival during hypoxia: ATP-sensitive K+ channels. Biol Neonate 65:160-5
Jiang, C; Haddad, G G (1994) A direct mechanism for sensing low oxygen levels by central neurons. Proc Natl Acad Sci U S A 91:7198-201
Jiang, C; Sigworth, F J; Haddad, G G (1994) Oxygen deprivation activates an ATP-inhibitable K+ channel in substantia nigra neurons. J Neurosci 14:5590-602

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