Common pathophysiological features in burning mouth syndrome and irritable bowel syndrome

Abstract: Irritable bowel syndrome (IBS), one of the intractable bowel diseases, is known to afflict 10%–15% of the population in developed countries. Intriguingly, burning mouth syndrome (BMS) which is famous as an intractable intra-oral sensory disorder and IBS are characterized by altered sensory qualities, namely pain hypersensitivity in IBS and BMS patients develops without any apparent pathological changes such as nerve injury, inflammation, trauma or malignant tumor in the gastrointestinal tract and oral mucosae. To illuminate these pathogenetic mechanisms, we developed a non-inflammatory model of lower gastrointestinal tract and tongue pain hypersensitivity in the mouse that reproduces these two important features (pain hypersensitivity and non-apparent pathological changes) of IBS and BMS. Firstly, colon pain hypersensitivity in the IBS was virtually absent in P2X3 knockout relative to wildtype mice. Intralumenal release of the endogenous P2X receptor ligand did not differ between wildtype and P2X3 knockout mice or change after the occurrence of IBS. The EC50 of P2X3 ligand for the fast current decreased in dorsal root ganglion (DRG) neurons innervating to gastrointestinal tract mucosa in the IBS. The enhancement of purinergic signaling in DRG neurons may contribute to colon pain hypersensitivity in the IBS. Secondary, we found that the increase of Artemin (Artn) mRNA expression in the tongue mucosa of BMS patients and the significant increase in Artn expression and heat hyperalgesia in the tongue mucosa in BMS model mouse. The transient receptor potential vanilloid 1 (TRPV1) antagonism or Artn neutralization inhibited the heat hyperalgesia. The increase of TRPV1-IR trigeminal ganglion (TG) neuron innervating the tongue was significantly reduced by Artn neutralization in the tongue mucosa. The TG neuronal hyperactivity was also inhibited by Artn neutralization These present findings suggest that the tongue Artn overexpression in the BMS causes heat hyper-responses in TG neurons via the TRPV1 hyperexpression, resulting in tongue heat hyperalgesia.