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.