Neurokinin 1 and 2 receptors are involved in PGE2- and citric acid-induced cough and ventilatory responses

Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E₂ (PGE₂, 0.43 mM) for 10 min in guinea pigs reportedly produces the distinct cough patterns (Type I vs. II) and ventilatory responses (long-lasting hyperventilation vs. brief tachypnea) even though triggering the same cough numbers. Type I and II coughs are primarily mediated by activation of TRPV1 and EP3 receptors (a PGE₂ receptor) of vagal C-fibers respectively. Substance P (SP) and neurokinin A (NKA) released by vagal pulmonary sensory fibers peripherally are capable of affecting CA-induced cough and ventilation via preferentially activating neurokinin 1 and 2 receptors (NK₁R and NK₂R) respectively. This study aimed to define the impacts of CA- and PGE₂-exposure on pulmonary SP and NKA levels and the roles of NK₁R and NK₂R in modulating CA- and PGE₂-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA- or PGE₂-exposure; (2) effects of CP-99994 and SR-48968 (a NK₁R and a NK₂R antagonist respectively) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA- and PGE₂-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NK₁R/NK₂R in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA- and PGE₂-exposure evoked Type I and II cough respectively associated with different degrees of increases in pulmonary SP and NKA. Applications of CP-99994 and SR-48968 via IP and IH efficiently suppressed the cough responses to CA with less impact on the cough response to PGE₂. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE₂. Moreover, NK₁R and NK₂R were always co-expressed in vagal C-neurons labeled by TRPV1 or EP3 receptors. These results suggest that SP and NKA endogenously released by CA- and PGE₂-exposure play important roles in generating the cough and ventilatory responses to CA and PGE₂, at least in part, via activation of NK₁R and NK₂R expressed in vagal C-neurons (pulmonary C-neurons).