5-HT₃receptors mediate inflammation-induced unmasking of functional tachykinin responses in vitro

Abstract

Exogenously applied tachykinins produce no measurable electrophysiological responses in the somata of vagal afferent neurons [nodose ganglion neurons (NGNs)] isolated from naive guinea pigs. By contrast, after in vitro antigen challenge of nodose ganglia from guinea pigs immunized with chick ovalbumin, approximately 60% (53 of 89) of NGNs were depolarized an average of 13 +/- 1.2 mV by substance P (SP; 100 nM; n = 53). Receptor antagonists and enzyme inhibitors were utilized to screen a number of mast cell-derived mediators for their role in the uncovering or "unmasking" of functional tachykinin receptors after antigen challenge. Two chemically distinct 5-hydroxytryptamine-3-receptor antagonists significantly reduced the percentage of NGNs displaying depolarizing SP responses. Treatment with Y-25130 (1 or 10 microM) or tropisetron (1 microM) 15 min before and during antigen challenge reduced the percentage of SP-responsive neurons to approximately 20 and approximately 15% respectively. These results suggest that activation of 5-hydroxytryptamine-3 receptors plays an integral role in the unmasking of functional tachykinin receptors after specific antigen challenge of nodose ganglia. The mediator(s) underlying tachykinin-receptor unmasking in the remainder of the NGNs has yet to be characterized. However, it does not appear to be histamine, prostanoids, or peptidoleukotrienes.

Glucose‐dependent trafficking of 5‐HT3 receptors in rat gastrointestinal vagal afferent neurons

“…In this regard, following ingestion of a meal, the levels of platelet-free 5-HT rise from approximately 25 to 88 nmol L )1,34 as vagal afferent neurons from several species, including the rat, display both 5-HT 2 and 5-HT 3 receptors, one may reasonable assume that vagal afferent neurons may be additionally excited by the increase in circulating 5-HT levels following ingestion of a meal. [21][22][23][24] In addition, therefore, to inducing the release of 5-HT from enterochromaffin cells and activating 5-HT 3 receptors on vagal afferent terminals within the GI tract, glucose may also increase the ability of vagal sensory neurons and nerve fibers to respond to the released 5-HT, providing a means by which the vagal afferent signal can be amplified and/or prolonged in a temporally distinct manner. Trafficking of 5-HT 3 receptors via regulated exocytosis has been shown previously to occur in expression systems, 35,36 but, to our knowledge, this is the first functional and physiological demonstration of 5-HT 3 receptor trafficking within peripheral neurons.…”

“…16,17 This phenomenon does not appear to be restricted to central vagal terminals, however, as vagal afferent neurons are also capable of altering their neurotransmitter phenotype in response to physiological conditions. [18][19][20] As vagal afferent neurons also display functional 5-HT 3 receptors [21][22][23][24] and are capable of responding to circulating blood glucose levels, this study aimed to determine whether extracellular glucose can modulate the response of GI vagal afferent neurons to 5-HT via alterations in 5-HT 3 receptor density and/or function.…”

Effects of central and peripheral depletion of serotonergic system on carrageenan-induced paw oedema

“…Different subtypes of 5HT receptors exist in sensory neurons which mediate inhibitory or stimulatory effects on SP release [21]. It has been shown that endogenous 5HT release and 5HT 3 receptor activation are critical for unmasking SP receptors in nodose neurons in allergic inflammation [22]. So it is possible that the pro-inflammatory effect of centrally 5HT mediated, at least partly, via interaction with 5HT 3 receptors on neurons which release SP.…”

Sensory Neural Targets for the Treatment of Cough

“…In guinea‐pigs, allergic inflammation leads to the ‘unmasking’ of neurokinin 2 (NK2) receptors on sensory nerves originating in the nodose ganglia 58 . This effect appears to be mediated by serotonin (via 5‐HT 3 receptors), which may be increased during inflammatory responses 59 . Although the functional consequences of these neurochemical alterations have yet to be fully described, changes in neurotransmitter phenotype and receptor expression may have profound influences on defensive reflex physiology.…”