Are Biogenic Amines Involved in Controlling Upper Airway Patency during REM Sleep
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《美国呼吸和危急护理医学》
University of Alberta Edmonton, Alberta, Canada
Obstructive sleep apnea (OSA) occurs in at least 9 to 15% of middle-aged adults, and it is likely that its prevalence will rise with the increasing incidence of obesity (1). OSA is associated with daytime somnolence, hypertension, heart failure, and cardiac arrhythmias. The pathophysiology of OSA is characterized by repetitive occlusions of the posterior pharynx during sleep due, in part, to decreased tone in the genioglossus muscle (2, 3). Nasal application of continuous positive airway pressure (CPAP) is the standard form of therapy for treating OSA. Although effective, many patients are unable to, or unwilling, to comply with the use of CPAP and thus there is intensive interest in developing effective pharmacologic therapies (4). However, such advances in therapy will necessitate a clear understanding of the neurochemical control of upper airway motoneurons during sleep–wake states. Two articles in this issue of the AJRCCM (pp. 1322–1330 and pp. 1338–1347) examine the state-dependent involvement of bioamines in the control of hypoglossal (XII) motoneuron excitability in rodent models, and provide important insights into potential pharmacologic interventions that may be useful in OSA.
Fenik and colleagues (5) tested the hypothesis that suppression of upper airway motor tone during REM sleep is due to reduced serotonergic (5-HT) and noradrenergic (NE) drive to XII motoneurons. Nerve recordings (XII nerve) were made from anesthetized rats to evaluate the effect of microinjection of antagonists to 1-noradrenergic (prazosin) and/or 5-HT (methysergide) receptors into the XII nuclei. The vagi were cut to accentuate baseline XII motor activity and REM-like sleep episodes were induced by injecting carbachol into the pontine reticular formation (6). The cocktail of NE and 5-HT receptor antagonists suppressed the baseline amplitude of XII motor discharge during anesthesia before administration of carbachol. This combination also blocked the suppression of XII motor discharge amplitude normally observed during the pharmacologically induced REM sleep–like state. The authors propose that a combined withdrawal of NE and 5-HT effects from XII motoneurons is the main factor underlying their reduced activity during REM sleep.
The novel demonstration of endogenous excitatory drive to XII motoneurons by NE extends past data that showed an excitatory effect of exogenously applied NE (7–9). Evidence of endogenous 5-HT release and excitation of XII motoneurons by applied 5-HT has been previously demonstrated by several studies using in vitro and in vivo models (8–12). It should also be noted that, in addition to 5-HT, raphe neurons contain the neurotransmitters glutamate, thyrotropin-releasing hormone, and substance P, all of which have excitatory actions on XII motoneurons (9). Thus, the modulation of these transmitters may contribute to changes in pharyngeal motor tone across sleep–wake states.
Fenik and colleagues' emphasis on the combinatorial actions of neuromodulators in controlling XII motoneuron excitability is particularly important. There is an increasing body of work demonstrating that XII motoneuronal excitability is dynamically modulated by neuromodulators that control multiple protein kinases and phosphatases (13). Indeed, targeting intracellular signal transduction cascades that regulate neuronal excitability downstream from the receptor may prove to be an effective pharmacologic strategy for OSA.
The second study reported in this issue, by Sood and coworkers (14), also examines the role of 5-HT in state-dependent control of XII motoneuron excitability. The chronically instrumented rat model developed in Dr. Horner's laboratory was used to measure genioglossus motor activity across natural sleep–wake states. The 5-HT receptor antagonist mianserin or MDL100907 was administered into portions of the XII motoneuron pool via microdialysis. In contrast to what was expected from past studies using more reduced preparations, Sood and colleagues demonstrate that the endogenous 5-HT drive affecting genioglossus activity is normally weak and minimally modulated with sleep state. This apparent contradiction is clarified by their demonstration that vagotomy, which is typical of reduced preparations including the carbachol model of REM sleep, significantly enhances 5-HT modulation of genioglossus activity. Thus, it appears that the potential role of 5-HT in modulating pharyngeal muscle activity might be overestimated in animal experiments using reduced, vagotomized preparations.
Sood and colleagues were careful to temper their conclusions regarding a lack of 5-HT–mediated events in OSA. They point out that 5-HT–mediated reflex compensations in certain patients with OSA, as well as the bulldog and Zucker rat models, could increase airway tone through 5-HT–mediated mechanisms. Indeed, there is evidence for 5-HT–induced plasticity of XII motoneuron activity in response to repeated bouts of intermittent hypoxia (13, 15) and decreased excitatory actions of 5-HT on XII motoneurons after long-term, intermittent hypoxia (16). It would be of interest to expand on the chronically instrumented rat model to examine the neurochemical control of XII motoneuron excitability after exposure to pathophysiologic aspects of OSA, such as airway obstruction and hypoxia.
Further basic neurophysiologic studies will be required to fully ascertain the role of biogenic amines and other neuromodulators controlling XII motoneuron excitability during sleep–wake states. These two studies demonstrate the necessity to consider converging, as well as interacting, neuromodulatory inputs and potential plasticity within the respiratory system, and also underline the need to consider data from multiple preparations before drawing conclusions about regulatory mechanisms.
FOOTNOTES
Conflict of Interest Statement: J.J.G. does not have a financial relationship with a commercial entity that has an interest in the subject matter of the manuscript.
REFERENCES
Ferini-Strambi L, Fantini ML, Castronovo C. Epidemiology of obstructive sleep apnea syndrome. Minerva Med 2004;95:187–202.
Gastaut H, Tassinari CA, Duron B. Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res 1966;1:167–186.
Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44:931–938.
Smith IE, Quinnell TG. Pharmacotherapies for obstructive sleep apnoea: where are we now Drugs 2004;64:1385–1399.
Fenik VB, Davies RO, Kubin L. REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 2005;172:1322–1330.
Kubin L. Carbachol models of REM sleep: recent developments and new directions. Arch Ital Biol 2001;139:147–168.
Funk GD, Smith JC, Feldman JL. Development of thyrotropin-releasing hormone and norepinephrine potentiation of inspiratory-related hypoglossal motoneuron discharge in neonatal and juvenile mice in vitro. J Neurophysiol 1994;72:2538–2541.
Al-Zubaidy ZA, Erickson RL, Greer JJ. Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats. Pflugers Arch 1996;431:942–949.
Bayliss DA, Viana F, Talley EM, Berger AJ. Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms. Respir Physiol 1997;110:139–150.
Fenik P, Veasey SC. Pharmacological characterization of serotonergic receptor activity in the hypoglossal nucleus. Am J Respir Crit Care Med 2003;167:563–569.
Kubin L, Tojima H, Reignier C, Pack AI, Davies RO. Interaction of serotonergic excitatory drive to hypoglossal motoneurons with carbachol-induced, REM sleep-like atonia. Sleep 1996;19:187–195.
Jelev A, Sood S, Liu H, Nolan P, Horner RL. Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats. J Physiol 2001;532:467–481.
Feldman JL, Neverova NV, Saywell SA. Modulation of hypoglossal motoneuron excitability by intracellular signal transduction cascades. Respir Physiol Neurobiol 2005;147:131–143.
Sood S, Morrison JL, Liu H, Horner RL. Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats. Am J Respir Crit Care Med 2005;172:1338–1347.
Fuller DD, Baker TL, Behan M, Mitchell GS. Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat. Physiol Genomics 2001;4:175–181.
Feldman JL, Janczewski WA. Slip of the tongue. Am J Respir Crit Care Med 2004;170:581–582.(John J. Greer, Ph.D.)
Obstructive sleep apnea (OSA) occurs in at least 9 to 15% of middle-aged adults, and it is likely that its prevalence will rise with the increasing incidence of obesity (1). OSA is associated with daytime somnolence, hypertension, heart failure, and cardiac arrhythmias. The pathophysiology of OSA is characterized by repetitive occlusions of the posterior pharynx during sleep due, in part, to decreased tone in the genioglossus muscle (2, 3). Nasal application of continuous positive airway pressure (CPAP) is the standard form of therapy for treating OSA. Although effective, many patients are unable to, or unwilling, to comply with the use of CPAP and thus there is intensive interest in developing effective pharmacologic therapies (4). However, such advances in therapy will necessitate a clear understanding of the neurochemical control of upper airway motoneurons during sleep–wake states. Two articles in this issue of the AJRCCM (pp. 1322–1330 and pp. 1338–1347) examine the state-dependent involvement of bioamines in the control of hypoglossal (XII) motoneuron excitability in rodent models, and provide important insights into potential pharmacologic interventions that may be useful in OSA.
Fenik and colleagues (5) tested the hypothesis that suppression of upper airway motor tone during REM sleep is due to reduced serotonergic (5-HT) and noradrenergic (NE) drive to XII motoneurons. Nerve recordings (XII nerve) were made from anesthetized rats to evaluate the effect of microinjection of antagonists to 1-noradrenergic (prazosin) and/or 5-HT (methysergide) receptors into the XII nuclei. The vagi were cut to accentuate baseline XII motor activity and REM-like sleep episodes were induced by injecting carbachol into the pontine reticular formation (6). The cocktail of NE and 5-HT receptor antagonists suppressed the baseline amplitude of XII motor discharge during anesthesia before administration of carbachol. This combination also blocked the suppression of XII motor discharge amplitude normally observed during the pharmacologically induced REM sleep–like state. The authors propose that a combined withdrawal of NE and 5-HT effects from XII motoneurons is the main factor underlying their reduced activity during REM sleep.
The novel demonstration of endogenous excitatory drive to XII motoneurons by NE extends past data that showed an excitatory effect of exogenously applied NE (7–9). Evidence of endogenous 5-HT release and excitation of XII motoneurons by applied 5-HT has been previously demonstrated by several studies using in vitro and in vivo models (8–12). It should also be noted that, in addition to 5-HT, raphe neurons contain the neurotransmitters glutamate, thyrotropin-releasing hormone, and substance P, all of which have excitatory actions on XII motoneurons (9). Thus, the modulation of these transmitters may contribute to changes in pharyngeal motor tone across sleep–wake states.
Fenik and colleagues' emphasis on the combinatorial actions of neuromodulators in controlling XII motoneuron excitability is particularly important. There is an increasing body of work demonstrating that XII motoneuronal excitability is dynamically modulated by neuromodulators that control multiple protein kinases and phosphatases (13). Indeed, targeting intracellular signal transduction cascades that regulate neuronal excitability downstream from the receptor may prove to be an effective pharmacologic strategy for OSA.
The second study reported in this issue, by Sood and coworkers (14), also examines the role of 5-HT in state-dependent control of XII motoneuron excitability. The chronically instrumented rat model developed in Dr. Horner's laboratory was used to measure genioglossus motor activity across natural sleep–wake states. The 5-HT receptor antagonist mianserin or MDL100907 was administered into portions of the XII motoneuron pool via microdialysis. In contrast to what was expected from past studies using more reduced preparations, Sood and colleagues demonstrate that the endogenous 5-HT drive affecting genioglossus activity is normally weak and minimally modulated with sleep state. This apparent contradiction is clarified by their demonstration that vagotomy, which is typical of reduced preparations including the carbachol model of REM sleep, significantly enhances 5-HT modulation of genioglossus activity. Thus, it appears that the potential role of 5-HT in modulating pharyngeal muscle activity might be overestimated in animal experiments using reduced, vagotomized preparations.
Sood and colleagues were careful to temper their conclusions regarding a lack of 5-HT–mediated events in OSA. They point out that 5-HT–mediated reflex compensations in certain patients with OSA, as well as the bulldog and Zucker rat models, could increase airway tone through 5-HT–mediated mechanisms. Indeed, there is evidence for 5-HT–induced plasticity of XII motoneuron activity in response to repeated bouts of intermittent hypoxia (13, 15) and decreased excitatory actions of 5-HT on XII motoneurons after long-term, intermittent hypoxia (16). It would be of interest to expand on the chronically instrumented rat model to examine the neurochemical control of XII motoneuron excitability after exposure to pathophysiologic aspects of OSA, such as airway obstruction and hypoxia.
Further basic neurophysiologic studies will be required to fully ascertain the role of biogenic amines and other neuromodulators controlling XII motoneuron excitability during sleep–wake states. These two studies demonstrate the necessity to consider converging, as well as interacting, neuromodulatory inputs and potential plasticity within the respiratory system, and also underline the need to consider data from multiple preparations before drawing conclusions about regulatory mechanisms.
FOOTNOTES
Conflict of Interest Statement: J.J.G. does not have a financial relationship with a commercial entity that has an interest in the subject matter of the manuscript.
REFERENCES
Ferini-Strambi L, Fantini ML, Castronovo C. Epidemiology of obstructive sleep apnea syndrome. Minerva Med 2004;95:187–202.
Gastaut H, Tassinari CA, Duron B. Polygraphic study of the episodic diurnal and nocturnal (hypnic and respiratory) manifestations of the Pickwick syndrome. Brain Res 1966;1:167–186.
Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44:931–938.
Smith IE, Quinnell TG. Pharmacotherapies for obstructive sleep apnoea: where are we now Drugs 2004;64:1385–1399.
Fenik VB, Davies RO, Kubin L. REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 2005;172:1322–1330.
Kubin L. Carbachol models of REM sleep: recent developments and new directions. Arch Ital Biol 2001;139:147–168.
Funk GD, Smith JC, Feldman JL. Development of thyrotropin-releasing hormone and norepinephrine potentiation of inspiratory-related hypoglossal motoneuron discharge in neonatal and juvenile mice in vitro. J Neurophysiol 1994;72:2538–2541.
Al-Zubaidy ZA, Erickson RL, Greer JJ. Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats. Pflugers Arch 1996;431:942–949.
Bayliss DA, Viana F, Talley EM, Berger AJ. Neuromodulation of hypoglossal motoneurons: cellular and developmental mechanisms. Respir Physiol 1997;110:139–150.
Fenik P, Veasey SC. Pharmacological characterization of serotonergic receptor activity in the hypoglossal nucleus. Am J Respir Crit Care Med 2003;167:563–569.
Kubin L, Tojima H, Reignier C, Pack AI, Davies RO. Interaction of serotonergic excitatory drive to hypoglossal motoneurons with carbachol-induced, REM sleep-like atonia. Sleep 1996;19:187–195.
Jelev A, Sood S, Liu H, Nolan P, Horner RL. Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats. J Physiol 2001;532:467–481.
Feldman JL, Neverova NV, Saywell SA. Modulation of hypoglossal motoneuron excitability by intracellular signal transduction cascades. Respir Physiol Neurobiol 2005;147:131–143.
Sood S, Morrison JL, Liu H, Horner RL. Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats. Am J Respir Crit Care Med 2005;172:1338–1347.
Fuller DD, Baker TL, Behan M, Mitchell GS. Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat. Physiol Genomics 2001;4:175–181.
Feldman JL, Janczewski WA. Slip of the tongue. Am J Respir Crit Care Med 2004;170:581–582.(John J. Greer, Ph.D.)