Repetitive airway occlusion during sleep, resulting in sleep apnea and concomitant hypoxemia, affects 2-5% of the adult population. The obstruction is most common in the oropharynx and is considered to result from anatomic abnormalities acting in concert with a failure of upper airway muscles to be properly activated during sleep. The frequency and severity of the apneas is often greatest during REM sleep, when a hypotonia of many airway muscles occurs in parallel with a generalized postural muscle atonia. This, together with the intermittent and nonuniform nature of the apneas, points to central nervous control as an important component of the syndrome, but the mechanisms are unknown. While the genioglossus muscle is often considered to be the most important muscle governing oropharyngeal patency, other muscles of the pharyngeal wall and palate may be equally (or more) important in allowing the obstruction to occur. To study the neural mechanisms underlying the atonia of upper airway muscles during sleep, an acute animal model has been developed whereby a muscle atonia that directly corresponds to the atonia of REM sleep can be produced pharmacologically, by injecting the cholinergic agonist carbachol into the pons, allowing dissection of the underlying mechanisms. Use of this model showed that the control of upper airway muscles differs from that of postural muscles in that disfacilitation (removal of excitation) plays the dominant role, not synaptic inhibition. This led to the current general hypothesis that disfacilitation from the excitatory effects of the aminergic neurons of the brainstem during REM sleep leads to upper airway atonia. Further, it is hypothesized that, due to differences in motoneuronal membrane receptors, this disfacilitation will lead to pharyngeal muscle activity being more strongly suppressed than laryngeal muscle activity. A variety of complementary physiological and pharmacological techniques (microelectrode recording, microinjection, microiontophoresis, microdialysis) will be used to test the effects of various neurotransmitters secreted by the aminergic neurons of the caudal raphe (serotonin, thyrotropin releasing hormone, substance P) and locus coeruleus complex (noradrenaline), and their specific receptor agonists and antagonists, on the excitability of motoneurons to different upper airway muscles. Motoneurons to pharyngeal, laryngeal, glossal and palatal muscles will be studied. Particular attention will be paid to qualitative and/or quantitative differences in the mechanisms of maintaining the activity in the different upper airway motoneuronal groups. The results of this project should provide a better understanding of the mechanisms underlying upper airway atonia during sleep and guide pharmacological approaches (not yet available) to the prevention and treatment of airway occlusions during sleep.
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