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

Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E (PGE, 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 PGE 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 (NKR and NKR) respectively. This study aimed to define the impacts of CA- and PGE-exposure on pulmonary SP and NKA levels and the roles of NKR and NKR in modulating CA- and PGE-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA- or PGE-exposure; (2) effects of CP-99994 and SR-48968 (a NKR and a NKR antagonist respectively) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA- and PGE-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NKR/NKR in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA- and PGE-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 PGE. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE. Moreover, NKR and NKR 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 PGE-exposure play important roles in generating the cough and ventilatory responses to CA and PGE, at least in part, via activation of NKR and NKR expressed in vagal C-neurons (pulmonary C-neurons).