Psychopharmacological modelling of ongoing visceral pain

Pain is both an unpleasant sensory and emotional experience, and both aspects need be accounted for by successful strategies to treat chronic pain. The emotional component is particularly relevant to chronic visceral pain because the cause of pain may remain unclear even after extensive diagnostic workup. Inflammatory bowel disease and functional visceral pain syndromes are associated with many psychosocial and psychiatric abnormalities and thought to arise from a disturbance of the bidirectional gut-brain axis. The prevalence of chronic visceral pain and its comorbidity with emotional-affective disturbances are of considerable socio-economic relevance, especially because the therapeutic opportunities are very limited. Although gastrointestinal hypersensitivity has been widely considered as a biomarker of ongoing (spontaneous) visceral pain, experimental assessment of this aspect by single reflexive rather than multiple operant readouts is likely to explain why there has frequently been a lack of translation between preclinical and clinical studies. Against this background it is the aim of the current experimental proposal to apply new concepts to the study of chronic visceral pain and its comorbidity with emotional-affective disturbances. The specific hypotheses to be addressed are that " ongoing visceral pain can be recorded by multiple operant readouts of the emotional-affective and cognitive behaviour, " ongoing visceral pain is reflected by changes in the visceral pain - mood axis, " enhanced anxiety and depressed mood modulate the visceral pain - mood axis, " endocrine signalling between the gut and brain is relevant to ongoing visceral pain, " the visceral pain-mood axis involves the hypothalamic-pituitary-adrenal system, and " these approaches will provide experimental models with enhanced translational power for testing drug candidates. The specific approaches to the hypotheses under study are " to use 3 experimental models of visceral hyperalgesia (stress, mild colitis, and mild colitis combined with stress) to establish readouts of ongoing visceral pain, " to portray multiple aspects of the visceral pain - mood axis via alterations of anxiety, mood, cognition and circadian activities, " to investigate neurochemical aspects of chronic visceral pain by in vivo microdialysis in the hippocampus, an area of prime relevance to emotion, affect and cognition, " to explore the dynamics of the HPA axis in relation to visceral hyperalgesia, and " to test some gut hormones such as peptide YY and melatonin, known to affect brain functions, for a possible implication in the visceral pain - mood axis. In these approaches, the proposal strives to establish experimental models for chronic visceral pain with face, construct and predictive validity.

Pain is both an unpleasant sensory and emotional experience, and both aspects need be accounted for by successful strategies to treat chronic pain. The emotional component is particularly relevant to chronic visceral pain because the cause of pain may remain unclear even after extensive diagnostic workup. Inflammatory bowel disease and visceral pain syndromes such as irritable bowel syndrome are associated with many psychosocial and psychiatric abnormalities and thought to arise from a disturbance of the bidirectional gut- brain axis. The prevalence of chronic visceral pain and its comorbidity with emotional- affective disturbances are of considerable socio-economic relevance, especially because the therapeutic opportunities are very limited. Experimental studies of chronic visceral pain have in the past been focussed on the hypersensitivity of peripheral nociceptive nerve fibres. Chronic visceral pain, however, often occurs in the absence of identified pain stimuli, which points to an aberrant pain processing in the brain and may explain why efforts to develop new pain medicines have frequently failed. Against this background it was the aim of the current project to study brain function and behaviour in experimental models of chronic abdominal pain and to analyse the endocrine, immunological and neurochemical perturbations that may underlie any changes in the brain. The results of the project demonstrate that inflammation-induced chronic abdominal pain is associated with molecular alterations in distinct brain regions as well as with distinct alterations of behaviour (anxiety, reduction in social interaction) and the stress response. Further analysis reveals that several signalling pathways between the gut and brain (endocrine, immunological, neuronal) are likely contribute to functional changes in the brain which may disturb behaviour and lead to the manifestation of chronic abdominal pain. A comprehension of chronic abdominal pain syndromes thus necessitates identification of all (not only neuronal) information channels between the periphery and brain. These signalling pathways will not only impact on pain processing, but also affect brain regions that are relevant to emotion, affect and stress, which may explain the comorbidity of chronic visceral pain with psychiatric disorders. The overall conclusion for follow-up studies is that normalization of the disturbed brain function associated with chronic abdominal pain is a prerequisite for successful therapy.