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Consecutive daily hypoxia in developing swine results in a relatively lower hyperventilatory response than does a single exposure to the same hypoxic protocol [1]. We have hypothesized that this relative hypoventilation is associated with a decreased excitatory versus inhibitory neuromodulatory influence on central integrative pathways of breathing control.  Among the many central neuromodulatory systems shown to influence respiration, our laboratory has focused on the excitatory substance P/neurotachykinin and on the inhibitory opioid systems, the natural peptides and receptors of which are found in central respiratory-related regions. During hypoxia, neuropeptide release from neurons into the interstitial brain space is enhanced. Theoretically, therefore, the increased extracellular ligand concentrations should enhance receptor activation. On the other hand, however, the signal transduction pathways of ligand-activated G-protein receptors, including the neurotachykinin and opioid receptors, entail temporary internalization of the receptors from the membrane into the cytoplasm, rendering them temporarily unavailable for further activation. Thus, the functionality of each neuromodulator system depends on the ratio of extracellular peptide molecules to the number of available receptors at any moment. We have asked whether a differential degree of receptor internalization between neurotachykinin and opioid receptors might contribute to the relatively diminished hypoxic response observed in developing piglets. To answer this question, we have first focused on the binding of neurotachykinin-1 receptors (NK-1R) and mu-opioid receptors (MOR) in the brainstem of the mature rat in response to recurrent or single episodic hypoxia as compared to normoxia. The hypoxia protocol was 6 episodes of 8% O2 -92% N2 for 5 min, each followed by 21% O2 -79% N2 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.

Central neuromodulation and adaptations during respiratory development