부산대학교 도서관

Oropharyngeal dysphagia (OD) is described as a disorder of the swallowing function and as difficulty or discomfort while safely and efficiently transporting the alimentary bolus and liquids from the mouth to the esophagus. OD is highly prevalent among older people, stroke patients, neurodegenerative or neuromuscular disease patients and patients with head and neck diseases or that undergo head and neck surgery. The management of these patients is currently based in compensating with thickeners, postures and maneuvers and the speech therapy, but there is no specific pharmacological treatment that improves the impaired physiology of these patients. With this Thesis we have set the bases for a new line of specific pharmacological treatments for OD by means of translational research, from basic research (histology and molecular biology) to clinical studies in which we assayed different treatments, by way of pharmacodynamic studies of these treatments. These new treatments are based in the sensory stimulation with pharmacological agonists of receptors found in the human oropharynx. This strategy aims to improve swallow by speeding the oropharyngeal swallow response (OSR) and strengthening lingual propulsion adding those agonists into the alimentary bolus. The human oropharyngeal mucosa structure is histologically different in the tongue (specialized mucosa) compared to the pharynx and epiglottis (lining mucosa). The oropharyngeal mucosa sensory innervation is generally found under the epithelium, although there are also nerve ends that penetrate the epithelium. TRPV1 and TRPA1 are expressed in the regions innervated by the CN V, IX and X, but while TRPV1 is mainly found on the epithelial cell membrane, TRPA1 is mainly found below the epithelium. TRPM8 is not expressed in the human oropharynx, but it is found on the nerve ends innervating the mucosa. ASIC3 is expressed in the regions innervated by the CN V, IX and X and it is found on the nerve ends innervating the mucosa. Capsaicin and piperine to a greater degree and natural capsaicinoids to a lesser degree successfully stimulate the TRPV1 channel. Repeated exposition of these agonists decreases the effect on TRPV1, suggesting desensitization. Moreover, their effect is significantly reduced by a TRPV1-specific antagonist, showing their action to be specific to this receptor. Supplementing nectar viscosity boluses with natural capsaicinoids has the greatest therapeutic effect on VFS signs and OSR compared with the dual TRPV1/A1 agonist, piperine, or the TRPM8 agonist, menthol. While TRP stimulants increased bolus velocity and reduced OSR times, thickeners reduce bolus velocity and further delay the OSR. This Thesis sets the bases for the development of a new generation of treatments for OD based in the stimulation of deglutition through the use of agonist of receptors found in the human oropharynx. In the future, the treatment for patients with OD caused by neurological disease and ageing will be personalized, involving the study of the physiopathology to select the best treatment; from compensation with current OD management to the rehabilitation of swallow function with future treatments.