Targeting Chemosensory Ion Channels in Peripheral Swallowing-Related Regions for the Management of Oropharyngeal Dysphagia

Abstract

Oropharyngeal dysphagia, or difficulty in swallowing, is a major health problem that can lead to serious complications, such as pulmonary aspiration, malnutrition, dehydration, and pneumonia. The current clinical management of oropharyngeal dysphagia mainly focuses on compensatory strategies and swallowing exercises/maneuvers; however, studies have suggested their limited effectiveness for recovering swallowing physiology and for promoting neuroplasticity in swallowing-related neuronal networks. Several new and innovative strategies based on neurostimulation in peripheral and cortical swallowing-related regions have been investigated, and appear promising for the management of oropharyngeal dysphagia. The peripheral chemical neurostimulation strategy is one of the innovative strategies, and targets chemosensory ion channels expressed in peripheral swallowing-related regions. A considerable number of animal and human studies, including randomized clinical trials in patients with oropharyngeal dysphagia, have reported improvements in the efficacy, safety, and physiology of swallowing using this strategy. There is also evidence that neuroplasticity is promoted in swallowing-related neuronal networks with this strategy. The targeting of chemosensory ion channels in peripheral swallowing-related regions may therefore be a promising pharmacological treatment strategy for the management of oropharyngeal dysphagia. In this review, we focus on this strategy, including its possible neurophysiological and molecular mechanisms.

Keywords: chemosensory ion channels; molecular mechanisms; neurophysiological mechanisms; oropharyngeal dysphagia; peripheral chemical neurostimulation strategy.

Figure 1

Possible transduction mechanisms and neurophysiological pathways of improving swallowing function via the actions of chemical stimuli applied to peripheral swallowing-related regions. Chemical stimuli applied to peripheral swallowing-related regions can activate chemosensory ion channels expressed in the epithelial cells and nerve fibers in these regions, causing the entry of ions into these structures. The epithelial cells may then release ATP, which can activate purinergic receptors expressed on nearby intra- or sub-epithelial afferent nerve fibers, thus causing the entry of ions into the nerve fibers, leading to the generation of action potentials. Action potentials in the nerve fibers may also be generated by direct ion entry into the nerves through the activation of chemosensory ion channels by chemical stimuli. The action potentials (sensory inputs) then travel via afferent pathways (the V, VII, IX, and X nerves) to the DSG of the sCPG, as well as to the sensory cortex and subcortical swallowing-related regions of the brain. Sensory inputs are then processed by the cortical and subcortical swallowing-related neuronal networks and the sCPG to execute the motor drive for swallowing. The motor output is conveyed to the peripheral swallowing-related muscles through the motor nuclei of the V, VII, IX, X, XII, and C1–C2 nerves. ATP: adenosine triphosphate; DSG: Dorsal swallowing group; SP: Substance P; sCPG: Swallowing central pattern generator; VSG: Ventral swallowing group; V: Trigeminal nerve; VII: Facial nerve; IX: Glossopharyngeal nerve; X: Vagus nerve; XII: Hypoglossal nerve; C1–C2: Cervical nerves 1–2. In the lower part of the figure: Yellow-colored solid lines indicate afferent pathways. Blue-colored solid lines indicate efferent pathways. Black-colored solid line indicates connection between sensory and motor cortex. Black-colored broken lines indicate interconnection among the regions.