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.

Results of Research

NMDA Receptor Antagonist Studies with Ketamine:

The results of these experiments have shown that low dose intravenous ketamine can prevent the acid induced visceral hypersensitivity in the oesophagus of healthy volunteers and more importantly reverse established visceral hypersensitivity. These studies have shown that the receptor mechanisms of visceral hypersensitivity are the same as those of somatic hypersensitivity i.e. skin. The experiments have also shown that this drug was acting at the spinal cord level and not at the brain or peripheral nerve level. Most subjects experienced mild side effects during the ketamine infusion in keeping with previous published studies of ketamine in somatic pain but no subject ceased the study due to side effects. These experiments have obvious clinical implications, since ketamine can reverse established hypersensitivity in healthy volunteers then ketamine-like drugs may have a role in reversing symptoms of visceral hypersensitivity in patients with FGD’s and such drugs are now in development by pharmaceutical companies.

Current & Future Studies and their Implications

Having shown that ketamine can both prevent and reverse the development of visceral hypersensitivity in healthy volunteers, I will be conducting experiments to assess if ketamine can reverse the hypersensitivity in the oesophagus of patients with non-cardiac chest pain. This is a condition in which patients have recurrent chest pain and have been shown to have no cardiac cause, but using our oesophageal model it has been shown that these patients have visceral hypersensitivity. Since the mechanism for visceral hypersensitivity will be the same throughout the digestive tract then this will also have implications for the potential treatment of patients with other forms of visceral hypersensitivity such as irritable bowel syndrome and functional dyspepsia.

Given the side effects of ketamine (due to its widespread effects on the brain as well as spinal cord), and given its intravenous mode of administration (oral ketamine absorption is notoriously unreliable), it would not be a clinically viable drug. However, the experiments I undertook were designed as mechanistic studies to determine “proof of principle” as to what receptors were involved in the development and maintenance of visceral hypersensitivity in our oesophageal model. The development of more specific ketamine-like compounds which act on the same receptor, but at the same time do not act on the brain, are currently in development by several pharmaceutical companies. These drugs hold significant promise for reversing established visceral hypersensitivity in patients with FGD’s and are an important avenue for future research which I will be exploring using human models of visceral pain.