Central mechanisms controlling upper airway patency
2001-08-17

Several key events in the development of the perinatal rat phrenic nerve and diaphragm have been determined, including the following: i) Fetal inspiratory motor discharge commences within the phrenic motoneuron (PMN) pool on embryonic day (E)17; gestation period is 21 days.ii) Phrenic axons grow to innervate the full extent of diaphragmatic musculature by E17-E18.iii) There is a radical maturation of PMN morphology during the period from E16-E20.We have subsequently gone on to examine functional changes by examining PMN electrophysiological and diaphragm contractile properties prior and subsequent to these pivotal developmental stages (E16-P0).Summary data will be presented demonstrating the following: 1) As PMNs develop from E16 to P0, there are changes in passive membrane properties; resting membrane potential becomes hyperpolarized by ~10 mV, the input resistance decreases ~3-fold, and the mean rheobase increases by a factor of ~2.6.2) There are significant changes in the amplitude, duration and the afterpotentials of action potentials from E16-P0 which places restrictions on the repetitive firing patterns of fetal PMNs.3) The changes in PMN firing properties are primarily due to age-dependent changes in the expression of voltage-sensitive calcium and calcium-activated potassium currents.4) Both dye and electrical coupling have been detected amongst subpopulations of PMNs between ages E16 and P0. 5) There are marked changes in diaphragm muscle contractile properties that develop in concert with PMN repetitive firing properties so that the full-range of diaphragm force recruitment can be utilized at each age and potential problems of diaphragm fatigue are minimized.Data presented will be derived from the following references: commentary review reports meeting abstracts primary research S3 lowed by 21% O 2 -79% N 2 for 5 min, either on 6 consecutive days (recurrent episodic hypoxia), or on the 6th day only, following 5 daily normoxic exposures (single episodic hypoxia).Brains were collected either 5 min or 2 h after the last gaseous exposure.Brainstem sections underwent autoradiography with iodinated substance P for NK-1R or DAMGO for MOR.In nucleus tractus solitarius (NTS) from brains collected 2 h after the last exposure, the binding densities of NK-1R and MOR were unaltered by a single episodic hypoxia, and were greatly increased after recurrent episodic hypoxia, indicating an upregulation of both receptors by the recurrent episodic stimulus.In the NTS from the brains collected 5 min after the last hypoxic exposure, there was an important discrepancy in the binding response between the NK-1R and the MOR: The NK-1R displayed a significant decrease in ligand binding after both single and recurrent episodic hypoxia, implying enhanced receptor internalization.In contrast, the binding of MOR was not changed, implying that the rate of receptor internalization was not altered by the hypoxic exposure.This difference would result in relatively greater availability of functional MOR to opioid peptides during hypoxia.At present, we are carrying out the same experiments in developing piglets, using the same hypoxia protocols.If the findings in piglets' brains (to be presented at the Satellite meeting) are the same as those in the adult rat brain, the greater availability of functional MOR as compared to NK-1R during hypoxia may explain the attenuated ventilatory response to repeated hypoxia during development in piglets.