Related Experiment Video
Updated: May 3, 2026
Optogenetic Manipulation of Neural Circuits During Monitoring Sleep/wakefulness States in Mice
Published on: June 19, 2019
Identification of a pharmacological target for genioglossus reactivation throughout sleep
Kevin P Grace1, Stuart W Hughes2, Richard L Horner3
1Department of Medicine, University of Toronto, Toronto, Canada.
Study Objectives:
Obstructive sleep apnea (OSA) is a significant public health problem caused by repeated episodes of upper airway closure that occur only during sleep. Attempts to treat OSA pharmacologically have been unsuccessful because there has not been identification of a target operating at cranial motor nuclei, blockade of which can reactivate pharyngeal muscle activity throughout sleep. Increasing potassium conductance is a common mechanism by which state-dependent neuromodulators reduce motoneuron excitability. Therefore, we aimed to determine if potassium channel blockade is an effective strategy to reactivate the pharyngeal musculature throughout sleep.
Design Participants And Interventions:
In rats chronically instrumented for recording sleep-wake states and respiratory motor activities, we locally microperfused pharmacological agents into the hypoglossal motor pool to modulate potassium channels of three major classes: inwardly rectifying, two-pore domain, and voltage-gated.
Measurements And Results:
Microperfusion of the inwardly rectifying potassium channel blocker, barium, as well as the voltage-gated potassium channel blockers, tetraethylammonium and 4-aminopyridine, increased tonic and respiratory-related genioglossus activities throughout nonrapid eye movement (non-REM) and rapid eye movement (REM) sleep to 133-300% of levels present during baseline wakefulness. In contrast, microperfusion of methanandamide (TWIK-related acid-sensitive potassium [TASK] channel blocker/cannabinoid receptor agonist) activated genioglossus in wakefulness but not in sleep.
Conclusions:
These findings establish proof-of-principle that targeted blockade of certain potassium channels at the hypoglossal motor pool is an effective strategy for reversing upper airway hypotonia and causing sustained reactivation of genioglossus throughout nonrapid eye movement and rapid eye movement sleep. These findings identify an important new direction for translational approaches to the pharmacological treatment of obstructive sleep apnea.
Insights
Targeting specific potassium channels in the hypoglossal motor pool can reverse airway collapse during sleep. This study shows blocking these channels reactivates pharyngeal muscles, offering a new treatment for obstructive sleep apnea (OSA).
Area of Science:
- Neuroscience
- Respiratory Physiology
- Pharmacology
Background:
- Obstructive sleep apnea (OSA) involves airway closure during sleep due to reduced pharyngeal muscle activity.
- Current pharmacological treatments for OSA are limited by a lack of identified targets in cranial motor nuclei.
- Potassium channels modulate motoneuron excitability, influencing muscle activity during different sleep states.
Purpose of the Study:
- To investigate if blocking specific potassium channels can reactivate pharyngeal muscles throughout sleep.
- To determine the efficacy of targeting potassium channels in the hypoglossal motor pool for OSA treatment.
Main Methods:
- Rats were instrumented to record sleep-wake states and respiratory motor activity.
- Pharmacological agents targeting inwardly rectifying, two-pore domain, and voltage-gated potassium channels were microperfused into the hypoglossal motor pool.
- Genioglossus muscle activity was measured during non-REM and REM sleep.
Main Results:
- Blockade of inwardly rectifying (barium) and voltage-gated (tetraethylammonium, 4-aminopyridine) potassium channels increased genioglossus activity during both non-REM and REM sleep (133-300% of wakefulness levels).
- Methanandamide, a TASK channel blocker, activated genioglossus during wakefulness but not during sleep.
- These findings demonstrate sustained reactivation of pharyngeal musculature.
Conclusions:
- Targeted blockade of specific potassium channels in the hypoglossal motor pool effectively reverses upper airway hypotonia.
- This strategy provides sustained reactivation of the genioglossus muscle throughout sleep, addressing a key issue in OSA.
- This research identifies a promising new direction for developing pharmacological treatments for obstructive sleep apnea.
Related Concept Videos
01:17Sedatives and Hypnotics Drugs: Miscellaneous Agents
Melatonin congeners like ramelteon (Rozerem) and tasimelteon (Hetlioz) selectively bind to melatonin receptors (MT1 and MT2) and thus mimic the actions of melatonin, a hormone that regulates sleep-wake cycles. Tasimelteon is primarily used for non-24-hour sleep-wake disorder, common in blind patients. They are also used to treat conditions like insomnia...
01:29Pharmacogenomics: Identification of New Drug Targets
01:31Skeletal Muscle Relaxants: Therapeutic Uses
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
01:24Centrally Acting Muscle Relaxants: Therapeutic Uses
Centrally acting drugs are classified into spasmolytic and antispasmodic drugs. Spasmolytic drugs such as baclofen, diazepam, and tizanidine inhibit spinal motor neurons and decrease muscle tone. Spasmolytic drugs are administered for severe and chronic spasms due to multiple sclerosis, cerebral palsy, stroke, and spinal cord and muscle injuries. However,...
01:24Sleep-Wake Cycles
NREM Sleep
NREM sleep comprises four progressive stages that seamlessly merge: