Mast cell-mediated long-lasting increases in excitability of vagal C fibers in guinea pig esophagus

Abstract

Several esophageal pathologies are associated with an increased number of mast cells in the esophageal wall. We addressed the hypothesis that activation of esophageal mast cells leads to an increase in the excitability of local sensory C fibers. Guinea pigs were actively sensitized to ovalbumin. The mast cells in the esophagus were selectively activated ex vivo by superfusion with ovalbumin. Action potential discharge in guinea pig vagal nodose esophageal C-fiber nerve endings was monitored in the isolated (ex vivo) vagally innervated esophagus by extracellular recordings. Ovalbumin activated esophageal mast cells, leading to the rapid release of approximately 20% of the tissue histamine stores. This was associated with a consistent and significant increase in excitability of the nodose C fibers as reflected in a two- to threefold increase in action potential discharge frequency evoked by mechanical (increases in intraluminal pressure) stimulation. The increase in excitability persisted unchanged for at least 90 min (longest time period tested) after ovalbumin was washed from the tissue. This effect could be prevented by the histamine H1 receptor antagonist pyrilamine, but once the increase in excitability occurred, it persisted in the nominal absence of histamine and could not be reversed even with large concentrations of the histamine receptor antagonist. In conclusion, activation of esophageal mast cells leads to a pronounced and long-lived increase in nociceptive C-fiber excitability such that any sensation or reflex evoked via the vagal nociceptors will likely be enhanced. The effect is initiated by histamine acting via H1 receptor activation and maintained in the absence of the initiating stimulus.

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

“…Our findings provide the first direct evidence for a sensitization effect of PGD 2 on esophageal vagal afferent subtypes. The observation that PGD 2 failed to evoke action potential discharges in esophageal nodose C fibers but substantially increased their excitability to esophageal distension is similar to our previous observation of a MC activation-induced effect on esophageal vagal afferents (32). Pretreatment with the DP 1 receptor antagonist BW A868C did not totally abolish, but significantly attenuated, MC activation-induced sensitization of esophageal nodose C fibers.…”

“…DP 1 receptor antagonist attenuated esophageal mast cell activation-induced mechanical hypersensitivity in esophageal nodose C fibers. Our previous study showed that 30 min of perfusion with OVA induces MC activation, as indicated by increased release of histamine in the tissue and decreased staining of tryptase-positive MCs in the esophagus (32). To clarify the role of the DP 1 receptor in mediating esophageal MC activation-induced sensitization of esophageal nodose C fibers, we tested the hypothesis that pretreatment with a DP 1 receptor antagonist prevented esophageal MC activation-induced mechanical hypersensitivity in esophageal vagal nodose C fibers.…”

“…Esophageal distension-evoked action potentials were compared before and after PGD 2 perfusion. According to our previous studies (32,33), the response to the particular stimulus was considered positive when the stimulus evoked an action potential discharge with a peak frequency of 3 Hz (in the fibers with no baseline activity) or a peak frequency at least three times the frequency of baseline activity. In esophageal nodose C fibers, 30 min of perfusion with PGD 2 (10 l) did not evoke action potential discharges (0.6 Ϯ 0.3 and 1.6 Ϯ 0.5 Hz at baseline and with PGD 2 , respectively) but substantially increased their responses to esophageal distension.…”

“…They may also cause short-and long-lasting changes in the excitability and phenotype of juxtaposed nerves (4), which leads to GI sensory/motor dysfunctions (3). Our previous study provided the first direct evidence that selective activation of tissue MCs leads to a profound and long-lasting increase in the excitability of nodose C fibers in the esophagus (32). Histamine H 1 receptor antagonists inhibit the increased mechanoexcitability of esophageal nodose C fibers when given prior to, but not after, MC activation.…”

“…Histamine H 1 receptor antagonists inhibit the increased mechanoexcitability of esophageal nodose C fibers when given prior to, but not after, MC activation. In addition, exogenous histamine initiates, but does not maintain, the potentiation effect of MC activation on esophageal nodose C fibers (32). This indicates that although histamine is essential, additional mediators are critical in this potentiation process.…”