Researcher: Dr Robert Willert, University of Manchester   

Fellowship: Two Year Research Fellowship – completed April 2003

Grant Total:

Patients are often referred to gastroenterologists due to chronic abdominal or stomach pain. In many cases no cause for the patient's pain is found despite extensive and often invasive and expensive investigations. These patients are then said to have a functional gastrointestinal disorder (FGD). Examples of such conditions are irritable bowel syndrome, functional dyspepsia and non-cardiac chest pain.

Recently it has been suggested that some of these patients may have an increased gastrointestinal sensitivity such that non painful stimuli (for example normal bowel movements) are perceived as painful compared with normal healthy volunteers. This is known as visceral hypersensitivity.

Evidence exists for this phenomenon of visceral hypersensitivity in patients with all FGD's but the underlying mechanisms remain unknown and no effective treatment exists. The aim of the research was to investigate what happens in the body in patients with visceral hypersensitivity and thereby discover potential drugs which may be of use in these conditions.

Here is Dr Willert's final report:

Aims of Research

Patients are often referred to gastroenterologists with chronic abdominal pain. In many cases no cause for the patient’s pain is found despite extensive and expensive investigations. These patients are then said to have a functional gastrointestinal disorder (FGD) such as irritable bowel syndrome, functional dyspepsia and non-cardiac chest pain.

Recently it has been suggested these patients may have an increased gastrointestinal sensitivity such that non painful stimuli (for example normal bowel movements) are perceived as painful compared with normal healthy volunteers. This is known as visceral hypersensitivity.

Evidence exists for this phenomenon of visceral hypersensitivity in patients with all FGD’s but the underlying reasons why they are more sensitive than others people remains unknown and no effective treatments currently exist. The aim of my research was to investigate the potential mechanisms involved in visceral hypersensitivity and thereby discover potential drug targets which may be of use in these conditions.

Although the mechanisms of human visceral hypersensitivity have not been previously investigated there is a wealth of data on human hypersensitivity and pain processing in the skin (somatic hypersensitivity). It is known that following injury or inflammation there is an enhanced sensitivity of nerves both at the site of injury (peripheral sensitisation) and also at the site adjacent to the injury due to increased activation of nerves at the spinal cord (central sensitisation). These processes can last long after the injury or inflammation has ceased and several receptors are involved in their development.

At Hope Hospital, University of Manchester, we have previously developed a human model of visceral hypersensitivity (Fig 1). Pain thresholds to electrical stimulation are measured in the upper and lower oesophagus before and after an acid infusion (injury) in the lower oesophagus in healthy volunteers. We have shown that not only do the pain thresholds fall at the site of acid injury in the lower oesophagus (peripheral sensitisation) but also the pain thresholds are reduced following in the upper oesophagus where there has been no acid exposure (central sensitisation). This therefore suggests that the acid injury in the lower oesophagus causes an enhanced activation of nerves in the spinal cord, so causing the pain threshold in the upper oesophagus to fall; this is therefore analogous to somatic central sensitisation. Using this human oesophageal model I designed studies to assess the ability of different drugs to prevent and reverse the development of visceral hypersensitivity in healthy volunteers.

In somatic pain hypersensitivity the key chemical in the body which is involved in the development and maintenance of central sensitisation is the N-Methyl-D-Aspartate (NMDA) receptor (Fig 2). Therefore, the focus of my research has been on assessing whether the NMDA receptor is also implicated in the development and maintenance of visceral hypersensitivity. I have used a drug called ketamine which blocks the effect of NMDA receptor to see if this could block the development of visceral hypersensitivity using our oesophageal model and then to see if the visceral hypersensitivity could be reversed once established.

As well as the NMDA receptor other molecules and receptors are involved in somatic hypersensitivity and I have studied other drugs that act on these too.