α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea
Gang Song, Chi-Sang Poon
Gang Song, Chi-Sang Poon
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Research Article Neuroscience Pulmonology

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

Abstract

Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug target, we show that the repurposed α2-adrenergic antagonist yohimbine potently reversed the depressant effect of REM sleep on baseline hypoglossal motoneuron activity (a first-line motor defense against OSA) in rats. Remarkably, yohimbine also restored the obstructive apnea–induced long-term facilitation of hypoglossal motoneuron activity (hLTF), a much-neglected form of noradrenergic-dependent neuroplasticity that could provide a second-line motor defense against OSA but was also depressed during REM sleep. Corroborating immunohistologic, optogenetic, and pharmacologic evidence confirmed that yohimbine’s beneficial effects on baseline hypoglossal motoneuron activity and hLTF were mediated mainly through activation of pontine A7 and A5 noradrenergic neurons. Our results suggest a 2-tier (impaired first- and second-line motor defense) mechanism of noradrenergic-dependent pathogenesis of OSA and a promising pharmacotherapy for rescuing both these intrinsic defenses against OSA through disinhibition of A7 and A5 neurons by α2-adrenergic blockade.

Authors

Gang Song, Chi-Sang Poon

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Figure 7

Activation of α2-adrenoceptors on A7 or A5 neurons impaired obstructive apnea–induced hLTF.

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Activation of α2-adrenoceptors on A7 or A5 neurons impaired obstructive ...
(A–C) Tracings of integrated genioglossus electromyogram (∫GG EMG) and diaphragm EMG (∫Dia EMG) in 1 urethane-anesthetized, spontaneously breathing rat. (A) Microinjection of the α2-adrenoceptor agonist clonidine at bilateral A7 region (~50 nl at 5 mM at each injection site) reduced baseline GG activity (∫GG EMG amplitude). See Supplemental Figure 1 for microinjection loci. (B) After microinjection of clonidine, episodic obstructive apnea (denoted by dots above the ∫GG EMG recording) elicited relatively weak reflexive facilitation of GG activity during each apnea episode with no evidence of hLTF (hypoglossal long-term facilitation) afterward. (C) After washout of clonidine (2–3 hours after microinjection), baseline GG activity returned to control level. Episodic obstructive apnea elicited much stronger reflexive facilitation of GG activity during each apnea episode, with pronounced long-term facilitation of the inspiratory-phasic component of GG activity afterward. Note that, in B and C, a tonic component of GG activity (shaded in light blue) was recruited during obstructive apnea, but this tonic component decayed rapidly after each obstructive apnea episode and did not exhibit long-term facilitation afterward. (D) Bar graphs (overlaid with individual data points) showing the significant adverse effects (P < 0.05, 2-way ANOVA with repeated measures) of clonidine injection at bilateral A7 (n = 8) or A5 (n = 6) region (vs. corresponding control values after washout) on baseline GG activity before episodic obstructive apnea (left panel), as well as the facilitation of GG activity during the first and last apnea episodes (middle panel) and at 5 and 40 minutes after the last apnea episode (right panel). In the middle panel, areas of the bar graphs shaded in light blue indicate the magnitudes of the tonic component that contributed to GG activity; balance of the same bar graphs (not shaded in light blue) indicate the magnitudes of the corresponding inspiratory-phasic component. *P < 0.05 between values as indicated, Tukey post-hoc test.