Potential role of acid sensing ion channels and 5-hydroxytryptamine receptors in a rat model of gastro-esophageal reflux disease

An ongoing week acidic reflux is well established for patients of gastro-esophageal reflux disease (GERD) with persistent symptoms in spite of a treatment with proton-pump inhibitors (PPIs). The mechanisms of acid induced activation of esophageal afferent nerves are not well understood. We investigated in a rat model of GERD described earlier [1] the expression of acid sensing ion channels (ASIC) and of 5-hydroxytryptamin receptor (HTR) subtypes in esophageal tissue homogenates by whole genome microarray analysis. Tissues of animals suffering from GERD showed a small, but significant increase in the expression of the ASIC-subtype 4 (3.8f, p < 0.001) and of HTR2A (3fold), HTR2B (6.6f), and HTR7 (9.3f) (< 0.001) compared to “normal” tissue. Thus, both – ASICs and distinct 5-HTR subtypes – were up-regulated during the inflammatory process in our rat model. The higher expression of ASIC4 was not found in tissues of animals treated with either STW5 (2 ml/kg) or with the PPI omeprazole (O) (30 mg/kg). Minor differences, especially in the magnitude of down regulation, were seen for the 5-HTR subtypes after treatment with STW5 and O. Interestingly serotonin is not only the ligand for 5-HTR subtypes, but also an inflammatory mediator which can activate ASICs in peripheral nerve tissue to activate a central pain response [2]. Thus results could explain pain sensations without ongoing acidic reflux via serotonin. We hypothesize that a down regulation of ASIC4 and 5-HTR-subtypes by the treatments plays a role for the fast pain relief in responders to PPIs and to STW5. Both receptor types form a communication network involved in pain signaling and are candidate targets likely to be important for a succesful pain treatment in GERD.

References:

[1] Ulrich-Merzenich et al. Planta medica 2014; 80: P204

[2] Wemmie JA et al. Nature Rev NeuroScience 2013; 14: 461 – 71