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mise à jour du
23 octobre 2003
Respiratory Research
2001; 2; 5; 286-294
The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea
Richard L Horner
Department of medecine and department of physiology
University of Toronto Canada
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Obstructive sleep apnoea (OSA) is a serious breathing problem that affects approximately 4% of adults. OSA is associated with increased risk for adverse cardiovascular events such as angina, myocardial infarction, stroke and daytime hypertension. It also has adverse effects on sleep regulation, producing excessive daytime sleepiness, impaired work performance and increased risk for vehicular accidents, and impaired ventilatory and arousal responses to hypoxia and hypercapnia. Overall, OSA is a significant public health problem, with adverse clinical, social and economic consequences.

Current treatments

A detailed critique and comparison of current treatments for OSA is outside the scope of the present review, but both surgical and nonsurgical approaches (e.g. continuous positive airway pressure [CPAP], oral appliances and weight loss) all have some success in reducing the severity of OSA. With the exception of CPAP, however, no current treatment is able to abolish apnoea effectively across all sleep states, and some treatments have only minimal effects. Nevertheless, although CPAP at appropriate pressure is effective in abolishing apnoea, patient compliance is a serious problem and impaired daytime function returns after missing only one night of treatment.

Sleep mechanisms are critical to obstructive sleep apnoea

Pharyngeal muscle tone Suppression of pharyngeal muscle activity in sleep is critical to OSA by producing a narrower airspace that is more vulnerable to collapse on inspiration. Anatomical factors that result in a narrowed upper airspace (e.g.pharyngeal fat deposition, hypertrophied adenoids and tonsils, retrognathia, micrognathia, macroglossia) predispose to OSA by reducing the critical pressure that is needed for suction collapse. Likewise, changes in respiratory control system stability and decreased lung volume in sleep may also play a role in OSA. Notwithstanding the importance of such factors in predisposing to OSA, it is important to emphasize that, regardless of the features an individual patient may have that predispose to OSA, the upper airway still remains open in wakefulness and closes only in sleep. This simplistic, yet important, observation highlights a crucial feature relevant to this review, namely that OSA is a disorder dependent on sleep mechanisms because occlusions occur only in sleep. By extension, even in individuals with structural narrowing of the upper airway, OSA is ultimately caused by the impact of brain sleep mechanisms on the processes that control motor outflow to the pharyngeal muscles, the tone of which is necessary and sufficient to keep the airspace open during wakefulness.


The asphyxic stimuli and suction pressures generated during airway obstruction in sleep do not activate the pharyngeal muscles sufficiently to relieve the obstruction if the patient does not arouse from sleep, further highlighting the significant role of sleep mechanisms in OSA. Importantly, OSA patients also exhibit increased genioglossus (GG) muscle activity during wakefulness, suggesting the presence of a neuromuscular compensatory mechanism that prevents upper airway collapse in those individuals with narrowed airways. Although the mechanisms producing this compensatory increase in pharyngeal muscle activity in OSA patients are unknown, it is significant that this compensatory reflex is present in wakefulness and its withdrawal in sleep precipitates OSA.


In order to understand the pathogenesis of OSA, it is important to identify the mechanism(s) that underlie the wakefulness stimulus' to the pharyngeal dilator muscles. Specifically, it is necessary to identify the neurochemical basis of the effects of sleep and wakefulness on both pharyngeal muscle tone and reflex responses, and especially the mechanisms that underlie the sleep-dependent loss of the neuromuscular compensation for the narrowed airspace (Fig. 1). Identifying the neural substrate(s) for the wakefulness stimulus for pharyngeal motor neurones, and preventing loss of this stimulus in sleep, may theoretically lead to prevention of the critical reduction in pharyngeal dilator muscle activity that ultimately precipitates OSA. The following text summarizes some of the brainstem mechanisms that may be involved in modulating pharyngeal muscle activity during sleep and awake states, and that may represent potential therapeutic targets in OSA. The discussion does not focus on the general field of pharmacological interventions in OSA (e.g. use of protriptyline, progesterone, theophylline, acetazolamide; for overview see), but for the reasons discussed above it is restricted to influences of sleep-state dependent neural systems.

[...] Conclusion

There have been several previous attempts in humans to increase upper airway muscle tone and to alleviate obstructive apnoeas by neurochemical approaches, and a resurgence of interest in these approaches has occurred as knowledge of the neural systems that affect pharyngeal motor control increases. To date, however, these clinical studies have met with only limited success, in large part because the basic mechanisms that underlie suppression of upper airway muscle activity in natural sleep, and the neurotransmitters and receptor subtypes that are importantly involved, have not yet been fully determined. Once these neural systems and receptors have been identified and their relative importance determined, however, it is expected that more rational and systematic approaches can be devised for the systemic administration of drugs in order to centrally modulate motor output to the pharyngeal muscles. Indeed, as in other disciplines (e.g. the continuing development of drugs for asthma, heart disease, etc.), an effective route for overcoming the many obstacles in this field will probably be forthcoming, especially after the basic physiological experiments guide the clinical and therapeutic approaches to target specific receptors.

From a clinical perspective, the importance of understanding basic neural mechanisms of pharyngeal motor control, especially the differences in neurobiology between non- REM and REM sleep, cannot be emphasized enough, both in adequate interpretation of clinical data and in planning therapeutic interventions. For example, if progressive inhibition or absence of facilitation significantly contributes to further GG muscle suppression from non-REM to REM sleep, then a suitable combination of neuropharmacological agents may be more beneficial to maintaining pharyngeal muscle tone in REM sleep than modulating a single neurotransmitter that may only be effective in non-REM sleep. The implication of this consideration is that any potential therapy may have to be tailored to the individual patient, based on whether their sleep-disordered breathing predominates in non-REM and/or REM sleep. Accordingly, all studies investigating potential treatments for sleep-disordered breathing should rigorously control for such variables that influence OSA, such as sleep stage and even body position in which apnoeas occur.