Topical ATP Application in the Peripheral Swallowing-Related Regions Facilitates Triggering of the Swallowing Reflex Involving P2X3 Receptors

Abstract The swallowing reflex is a critical component of the digestive process, triggered when food or liquids pass from the oral cavity to the oesophagus. Although adenosine triphosphate (ATP) is involved in various physiological processes, its potential to trigger the swallowing reflex has not been fully explored. This study investigated the ability of ATP to induce the swallowing reflex and examined the involvement of the purinoreceptor P2X3 in this process. We observed that the topical application of exogenous ATP to the superior laryngeal nerve (SLN)-innervated swallowing-related regions dose-dependently facilitated the triggering of the swallowing reflex. P2X3 receptors were predominantly localized on nerve fibres within these regions, including intraepithelial and subepithelial nerves and those associated with taste-bud-like structures. In the nodose–petrosal–jugular ganglionic complex, approximately 40% of retrogradely traced SLN-afferent neurons expressed P2X3, with 59% being medium-sized, 30% small, and 11% large. Prior topical application of a P2X3 antagonist in SLN-innervated, swallowing-related regions significantly reduced the number of ATP-induced swallowing reflexes. Furthermore, topical application of a P2X3 receptor agonist more selective than ATP facilitated reflex triggering in a dose-dependent manner. These findings suggest that exogenous ATP facilitates the triggering of the swallowing reflex through the activation of P2X3 receptors. This activation excites afferent neurons that supply peripheral swallowing-related regions, stimulating the swallowing central pattern generator to facilitate the reflex. The current findings suggest the therapeutic potential of ATP or P2X3 agonists for dysphagia treatment and provide valuable physiological insights into the involvement of purinergic signaling in triggering the swallowing reflex.