PIs: Professor Qasim Aziz; Mr Charlie Knowles; Professor Daniel Sifrim; Dr D Bulmer

Collaborators: Professor Anthony Dickenson, Professor Stafford Lightman, Professor Steven Williams, Professor Paul Furlong

Visceral pain is one of the commonest symptoms encountered in medical practice. While its cause is obvious in structural (organic) disorders of the GI tract, in disorders of GI function the organ(s) involved and the pathophysiological mechanisms are still unclear and are likely to include both peripheral and central factors. It is not surprising therefore that management of pain in these latter conditions is often inadequate causing considerable morbidity and health care costs.

Our aim is to identify mechanisms of pain in health and disorders of GI function and to develop homogenous patient cohorts so that treatment can be stratified according to mechanisms of disease. More specifically we study:

• Mechanisms
  using use preclinical (in vivo and in vitro rodent models and in vitro human nerve gut preparations) and clinical models to identify molecular, and neurophysiological biomarkers of neuropathic and/or inflammatory pain and the role of psychological factors in the perception of visceral pain in health and disease. We are particularly interested in the role of peripheral injury and inflammation in the development of peripheral and central sensitisation and the role of relevant modulatory factors such as the autonomic nervous system and psychological factors. We have pioneered the use of functional brain imaging techniques such as functional magnetic resonance imaging and cortical evoked potentials to objectively study the role of the brain gut axis in visceral pain.
• Cohort development
  the main objective is to identify the psycho-physiological endophenotypes that carry different a risk for the development of chronic visceral pain. For instance our current MRC funded research suggests that healthy subjects with high neuroticism score generate a parasympathetic response to acute visceral pain and are more pain sensitive. We are determining if this psychophysiological profile is a risk factor for the development of chronic visceral pain. This programme will help to define patient cohorts with similar endophenotypes for clinical trials of visceral analgesics. Furthermore, genome wide analysis will be performed in the above defined endophenotypes to determine the genetic factors that predispose to chronic pain.
• Treatment
  we use a mechanistic approach to the treatment of visceral pain through the use of strategies specifically targeting homogenous patient groups. Existing and novel analgesics and neuropathic pain drugs are being trialled in preclinical and clinical models of visceral pain to identify those with most promise before trials in well characterised patient cohorts. For instance, patients with neuropathic pain will be treated with specific anti-neuropathic pain drugs rather than antispasmodics as is the current norm.

Strengths

1. Access to both preclincial and clinical models to study mechanisms of visceral pain and a multidisciplinary research group with wide ranging expertise. The models include rodent in-vivo and in-vitro, human tissue in-vitro and human in-vivo models to study molecular and neurophysiological aspects of visceral pain.
2. Excellent basic science and clinical laboratory facilities with ability to translate from rodents to human tissue and finally man and vice versa.
3. Access to large clinical populations with a large referral base for all aspects of functional gastrointestinal disorders.
4. Close co-operation with the Barts and The London Clinical Trials Unit for clinical trials ranging from proof of concept to phase III studies.
5. Funding from diverse sources including charitable foundations especially MRC, Humane Research organisations, ie, Hadwen Trust and Industry.

References

1. Aziz Q, DG Thompson, VWK Ng, S Hamdy, S Sarkar, MJ Brammer, ET Bullmore, AR Hobson, I Tracey, J Suckling, A Simmons and SCR Williams. Cortical processing of human somatic and visceral sensation. J Neurosci 2000; 20: 2657-63.
2. Sarkar S, Q Aziz, CJ Woolf, AR Hobson and DG Thompson. Central sensitization may contribute to the development of noncardiac chest pain. Lancet 2000; 356: 1154-9.
3. Phillips ML, LJ Gregory, S Cullen, SJ Coen, V Ng, C Andrew, V Giampietro, E Bullmore, F Zelaya, E Amaro, DG Thompson, AR Hobson, SCR Williams, M Brammer, Q Aziz. The effect of negative emotional context on neural and behavioural responses to oesophageal stimulation. Brain 2003; 126: 669-84.
4. Yaguez L, Gregory LJ, Aziz Q. Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study. Gastroenterology 2005; 128: 1819-29.
5. Hobson AR., Furlong PL., Worthen SF., Hillebrand A., Barnes GR., Singh KD and Aziz Q. Real-time imaging of human cortical activity evoked by painful esophageal stimulation. Gastroenterology 2005; 128: 610-9.
6. Hobson AR., Furlong PL., Sarkar S., Matthews PJ., Willert RP., Worthen SF., Unsworth BJ and Aziz Q. Neurophysiologic assessment of esophageal sensory processing in noncardiac chest pain. Gastroenterology 2006; 130: 80-8.
7. Coen SJ, Aziz Q, Yágüez L, Brammer M, Williams SC, Gregory LJ Effects of attention on visceral stimulus intensity encoding in the male human brain.. Gastroenterology 2008; 135: 2065-74.
8. Matthews PJ, Knowles CH, Chua YC, Delaney C, Hobson AR, Aziz Q. Effects of the concentration and frequency of acid infusion on the development and maintenance of esophageal hyperalgesia in a human volunteer model. Am J Physiol Gastrointest Liver Physiol 2008; 294: G914-7.
9. Coen SJ, Yágüez L, Aziz Q, Mitterschiffthaler MT, Brammer M, Williams SC, Gregory LJ. Negative mood affects brain processing of visceral sensation. Gastroenterology 2009; 137: 253-61, 261.e1-2.
10. Paine P, Worthen SF, Gregory LJ, Thompson DG, Aziz Q. Personality differences affect brainstem autonomic responses to visceral pain. Neurogastroenterol Motil 2009; 21: 1155-e98.