Allergic inflammation awakens silent tachykinin receptors in sensory neurons

Abstract

Bi-directional communication between the immune and nervous systems serves to amplify the inflammatory response. Inflammation increases neuronal activity which in turn augments the release of inflammatory mediators. This cascade, termed 'neurogenic inflammation', plays a role in a number of disease states, including asthma and inflammatory bowel disease. Vagal afferent neurons convey information from a number of organs afflicted by these diseases (lungs and gastrointestinal tract) to the CNS. Thus, vagal afferents are likely targets for modulation by immune cell-derived mediators. Immunologically sensitized guinea pigs exposed to aerosolized antigen are often used as a model for allergic airway inflammation. Utilizing this model, we have identified inflammation-induced changes in the tachykinin responsiveness of vagal afferents (nodose ganglion neurons; NGNs). NGNs isolated from normal guinea pigs are unresponsive to tachykinins (substance P (SP) and neurokinin A (NKA)). In contrast, following airway inflammation, SP depolarizes 80% of NGNs. Inflammation-induced changes in SP responsiveness were significantly attenuates by unilateral vagotomy, suggesting that the vagus nerve transmits critical signals from the airway to nodose ganglia. To study the cellular mechanisms of tachykinin receptor regulation, nodose ganglia isolated from 'sensitized' guinea pigs were employed. Nodose ganglion mast cells can be activated in vitro by challenging ganglia with the sensitizing antigen. This in vitro procedure mimics in vivo allergic airway inflammation; SP, acting via NK-2 tachykinin receptors, depolarizes 80% of NGNs. In vitro up-regulation or 'unmasking' of NK-2 receptors occurs within minutes and is independent of new protein synthesis, indicating that NK-2 receptors are present, but non-functional, in control NGNs. Acutely isolated NGNs were utilized to identify inflammatory mediators that unmask tachykinin receptors. Following a five minute incubation with serotonin (5-HT), SP depolarized 65% of NGNs. Pharmacological analysis revealed that 5-HT3 receptor activation, Ca2+i, and NO are requisite for this process. Antagonism of 5-HT3 receptors during in vitro antigenic activation of nodose ganglia significantly reduced the percentage of SP responsive neurons, confirming that 5-HT 3 receptor activation is essential for allergic inflammation-induced tachykinin receptor unmasking. The unmasking of NK-2 receptors is a novel mechanism of primary afferent neuron sensitization which may contribute to the development of pain commonly associated with inflammation.