Substance P–expressing neurons in the hypothalamic paraventricular nucleus mediate chronic cough hypersensitivity via the hypothalamus–airway neural pathway

Background and purpose Increased cough sensitivity is the key pathophysiological mechanism of chronic cough. Although previous studies have focused on peripheral airway receptor sensitization, the role of the central nervous system—particularly the hypothalamic paraventricular nucleus (PVN)—remains unclear. Whether substance P (SP)–expressing PVN neurons contribute to cough hypersensitivity remains unknown. Methods Three-week-old Hartley guinea pigs were divided into three groups: citric acid (CA), saline control (SA), and blank control (CON). A cough hypersensitivity model was induced by inhalation of 0.4 mol/L citric acid. Cough sensitivity was assessed using a capsaicin challenge, with the C5 threshold defined as the lowest capsaicin concentration inducing ≥5 coughs. Locomotor activity was evaluated using the open-field test. Airway inflammation and goblet cell hyperplasia were examined by HE and PAS staining. SP and c-Fos expression in the PVN were detected by immunofluorescence and Western blot. HSV retrograde tracing was used to analyze the PVN-airway neural pathway associated with cough hypersensitivity. Results Compared with the control groups, guinea pigs in the CA group exhibited a time-dependent increase in cough frequency and enhanced cough sensitivity, as indicated by a reduction in the C5 threshold. Histological analysis revealed increased inflammatory cell infiltration and goblet cell hyperplasia in the airways of the CA group. SP and c-Fos expression, along with the proportion of SP/Fos double-labeled neurons in the PVN, were significantly increased in the CA group (all P 0.05). Viral tracing confirmed the presence of HSV-positive neurons in the PVN, supporting a neural connection between the PVN and the airways. Conclusion Activation of SP-expressing neurons in the PVN is associated with cough hypersensitivity and suggests the presence of a potential PVN–airway neural pathway. These findings provide a theoretical basis for the development of central-targeted therapies for chronic cough.