Peripheral and central mechanisms in acid induced visceral pain hypersensitivity in the human oesophagus

Abstract

PhDIntroduction: Gastro-oesophageal reflux disease (GORD) affects 40% of Western populations. Many symptoms persist despite the resolution of inflammation or acid exposure. In these patients, visceral pain hypersensitivity (VPH), modulated peripherally and centrally, is believed to be important. Study 1: Full thickness human oesophageal samples were collected from 10 patients undergoing oesophagectomy. Using immunohistochemistry, the samples were stained with PGP 9.5, synapthophysin, TRPV1, TRPV4 and ASIC3. Within healthy areas of the human oesophagus, immunoreactive nerve fibres and ganglia were identified in the sub-epithelium and myenteric plexus. Within the epithelium, nerve endings were absent; however, ASIC3 was reliably identified in epitheliocytes. Study 2: Oesophageal biopsy samples from 36 individuals were collected during upper GI endoscopy; erosive oesophagitis, non-erosive reflux disease and controls. Symptoms were profiled using symptom severity scores, adapted from a validated questionnaire. Oesophageal mucosal biopsies were taken 3-5 cm above the lower oesophageal sphincter. Specific features of oesophageal mucosal epithelial ASIC3 were identified by immunohistochemistry, which were associated positively with an increase in symptom severity. Study 3: Oesophageal VPH can be induced in healthy volunteers using an established model of acid infusion. In total, 85 retrospective infusions from 57 volunteers were studied, and VPH was present in 70%. The model was shown to be safe and reproducible, but reliability of the model for drug studies was only valid provided control measures were observed. Study 4: Pregabalin is a centrally acting calcium channel blocker currently used for somatic neuropathic pain and partial seizures. Using the model described in study 3, a prospective, double-blinded, cross-over, placebo-controlled study in 15 healthy volunteers was performed. After an initial screening visit, the volunteers were randomised to either pregabalin or placebo. Pregabalin prevented or attenuated VPH at 30 and 90 minutes after acid sensitisation. Conclusion: The evidence for central sensitisation was further consolidated with the pregabalin study and peripheral sensitisation by the ASIC3 study. The evidence is important in the detection of predominant mechanisms underlying the symptoms of patients with GORD for both cohort development and targeted treatment