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Endogenous Excitatory Drive Modulating Respiratory Muscle Activity across Sleep–Wake States

Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Richard L. Horner, Ph.D., Room 6368 Medical Sciences Building, 1 Kings College Circle, Toronto, ON, Canada M5S 1A8. E-mail: richard.horner{at}utoronto.ca

Rationale: The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotransmitter substrate mediating respiratory muscle activation across sleep–wake states has not been identified.

Objectives: We determined if ₁ receptor antagonism at the hypoglossal motor nucleus (HMN) decreases genioglossus (GG) activity consistent with a role for an endogenous noradrenergic drive contributing to GG activation across sleep–wake states. We also determined if ₁ receptor stimulation could counteract reduced endogenous noradrenergic drive and increase sleeping GG activity.

Methods: Thirty-five rats were implanted with electroencephalogram and neck electrodes to record sleep–wake states and GG and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN.

Measurements and Main Results: Microdialysis perfusion of the ₁ receptor antagonist terazosin into the HMN significantly decreased GG activity in wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. The ₁ receptor agonist phenylephrine increased GG activity in wakefulness and sleep, but periods of motor inactivity persisted in REM sleep; there was no potentiating effect of combined ₁ and 5-HT₂ receptor stimulation.

Conclusions: Identification of an endogenous noradrenergic drive contributing to GG activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and obstructive sleep apnea in humans and the potential for pharmacologic treatment.

Key Words: genioglossus muscle • hypoglossal motor nucleus • noradrenaline • obstructive sleep apnea • serotonin • sleep

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Suppression of respiratory muscle activity in sleep is central to the pathogenesis of sleep-disordered breathing. However, the mechanisms modulating respiratory muscle activity across sleep–wake states had not been determined. What This Study Adds to the Field We identify an endogenous excitatory drive contributing to the maintenance of respiratory muscle activity in wakefulness and sleep. This article also has wider implications to other clinical problems of motor control in sleep, e.g., narcolepsy.

 

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