Sleep & Breathing

Abstract

Obstructive sleep apnoea is a common condition affecting, it is estimated, 4 % of middle-aged men and 2 % of middleaged women (Young et al. 1993). The pathogenesis of the disorder seems to involve anatomical compromise of the dimensions of the upper airway that are apparent even during wakefulness, which, when combined with the reduction or loss of upper airway dilator muscle activity during sleep, leads to airway closure (obstructive apnoea). Thus study of the neuronal mechanisms that result in reduction of airway dilator muscle activity during sleep is important in understanding the pathogenesis of the disorder.Studies in humans have documented that there is a reduction with sleep of motor activity in relevant upper airway muscles and virtual abolition of the reflex response to negative intraluminal pressure. However, studies in humans do not allow us to dissect basic mechanisms. Our research group has, therefore, taken advantage of the model that can be used in decerebrate animals whereby microinjection of the muscarinic agonist , carbachol, into the pontine tegmentum activates the cholinoceptive cells that are believed to produce the atonia of rapid eye movement (REM) sleep (for review of our results, see Kubin et al. 1998). When carbachol is microinjected, a stereotypical pattern of response in different respiratory motor outputs is observed . Phrenic nerve activity is least affected, intercostal nerve activity more affected, but there is a massive reduction in activity of the hypoglossal nerve (i.e. to upper airway dilator muscles). Laryngeal nerve activity is, however, relatively preserved. This stereotypical pattern is very similar to the differential effects that occur in normal sleep.This model allows study of the underlying mechanisms of at least this component of what occurs during REM sleep. Our studies reveal that, unlike lumbar motor neurons where there is fast synaptic inhibition mediated by glycine during both natural REM sleep and following carbachol microinjection, fast synaptic inhibition plays a minor, if any, role in the reduction of activity of hypoglossal motoneurons. Rather, our studies reveal that reduction in a facilitatory input mediated by serotonin (5-HT) plays an important role. Levels of 5-HT in the hypoglossal motor nucleus decline following carbachol microinjection. This facilitatory effect of 5-HT seems to be mediated by 5-HT 2A and 5-HT 2c receptors . Micropunch studies of the motor nucleus followed by RT-PCR reveal that these receptor subtypes are present in the motor nucleus. The current direction of our research is to investigate the cellular mechanisms activated by 5-HT in more detail and to study the role of other important sleeprelated neurotransmitters, in particular noradrenaline.This work was supported in part by NIH grant HL-42236. Physiology (1998) Several endogenous molecules including interleukin -1, TNF (and other immunomodulatory cytokines), delta-sleepinducing peptide and prostaglandin PGD 2 are CNS depressants. Humoral factors contributing to regulation of s...