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

Sensitization of esophageal afferents plays an important role in esophageal nociception, but the mechanism is less clear. Our previous studies demonstrated that mast cell (MC) activation releases the preformed mediators histamine and tryptase, which play important roles in sensitization of esophageal vagal nociceptive C fibers. PGD₂ is a lipid mediator released by activated MCs. Whether PGD₂ plays a role in this sensitization process has yet to be determined. Expression of the PGD₂ DP₁ and DP₂ receptors in nodose ganglion neurons was determined by immunofluorescence staining, Western blotting, and RT-PCR. Extracellular recordings were performed in ex vivo esophageal-vagal preparations. Action potentials evoked by esophageal distension were compared before and after perfusion of PGD₂, DP₁ and DP₂ receptor agonists, and MC activation, with or without pretreatment with antagonists. The effect of PGD₂ on 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal nodose neurons was determined by patch-clamp recording. Our results demonstrate that DP₁ and DP₂ receptor mRNA and protein were expressed mainly in small- and medium-diameter neurons in nodose ganglia. PGD₂ significantly increased esophageal distension-evoked action potential discharges in esophageal nodose C fibers. The DP₁ receptor agonist BW 245C mimicked this effect. PGD₂ directly sensitized DiI-labeled esophageal nodose neurons by decreasing the action potential threshold. Pretreatment with the DP₁ receptor antagonist BW A868C significantly inhibited PGD₂ perfusion- or MC activation-induced increases in esophageal distension-evoked action potential discharges in esophageal nodose C fibers. In conclusion, PGD₂ plays an important role in MC activation-induced sensitization of esophageal nodose C fibers. This adds a novel mechanism of visceral afferent sensitization.