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Wellcome Trust conference The Challenges of Chronic Pain

11-13 March 2015
Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

Abstract deadline: 30 January 2015
Registration deadline: 16 February 2015

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Europain consortium receives EU and industry funding and begins five year research into better treatments for chronic pain Europain, a public-private consortium funded by the Innovative Medicines Initiative (IMI), announced today the launch of a five-year research project to understand and improve treatment of chronic pain. The project will receive 6M€ from the IMI as well as 12.5M€ in kind contribution from the European Federation of Pharmaceutical Industries and Associations (EFPIA) over the coming five years.

One in five adults suffers from chronic pain. This constitutes a major cause of long-term sick leave and forced early retirement, placing a great financial burden on both individuals and healthcare systems. Despite extensive research programmes by biopharmaceutical companies and academia, there remains a need for treatments that are more effective and with fewer side-effects.

Europain has established an international team of leading researchers and clinicians from both academia and industry to undertake multidisciplinary translational research. This team aims to increase the understanding of chronic pain mechanisms, help to develop novel analgesics, and develop better biomarkers for pain. Their ultimate goal is to improve the lives of people suffering from chronic pain.

During the five-year project, Europain will undertake a large number of preclinical and clinical studies. The program will be delivered through collaboration between laboratories in the Europain network, sharing resources to improve the value derived from the budget. Results will be made public during and after the project, ensuring that the knowledge created can be widely applied to the development of better therapies for patients suffering from chronic pain.

King’s College London, the managing entity of Europain and the academic lead institution will contribute to both the pre-clinical and clinical aspects of the project. One role will be to study the expression of potential pain mediators in both animal models of pain and samples from patients suffering from chronic pain. The role of novel pain mediators will then be investigated using an array of techniques ranging from cell culture to quantitative sensory testing in humans.

Professor Steve McMahon, who along with Dr Dave Bennett will be running the project at King’s, comments: ‘There are some big questions facing the pain field at the moment and this consortium, drawing on the skills and expertise of both academia and industry, is in a unique position to address them’.

The consortium network involves scientists representing 12 renowned European Universities: King’s College London (Academic lead), University College London, Imperial College London, the University of Oxford, the Christian-Albrechts-University of Kiel, the Medical Faculty Mannheim/Heidelberg University, the Technische Universität München, the Goethe University of Frankfurt, the BG University Hospital Bergmannsheil/Ruhr University Bochum, the University Hospitals of Aarhus, Rigshospitalet Copenhagen, University of Southern Denmark, the SME Neuroscience Technologies from Barcelona, and the research resources and expertise of Europe’s most active pharmaceutical companies working in the field of analgesics, including AstraZeneca (co-ordinator), Boehringer-Ingelheim, Eli Lilly, Esteve, Pfizer, Sanofi-Aventis, UCB Pharma.

About the Innovative Medicines Initiative

IMI is a unique Public-Private Partnership (PPP) between the pharmaceutical industry represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the European Union represented by the European Commission.
Past Research
Characterisation of mouse dorsal horn organisation
Our studies on how the CNS adapts and responds to different sensory modalities and duration of stimuli have important neurobiological implications, but in more general terms can also aid both the treatment of pain and the development of novel analgesics 1-3. The challenge is to combine physiological and pharmacological techniques to study the integrated function of the nervous system in the context of sensory events related to the clinical problem of pain. In collaboration with John Wood in Biology, UCL we are also studying "knock-out" animals - genetically manipulated mice such that specific receptor/channel systems are lacking - valuable research tools. With Steve Hunt in Anatomy at UCL we are using ?molecular microsurgery? to delete specified neuronal groups in sensory pathways.

In an extensive behavioural study, using common assays of thermal, chemical and mechanical nociception, it is clear that between different strains of inbred mouse there is considerable variation in the sensitivity to noxious stimuli, neuropathic tendencies and pharmacological sensitivities 4. This variation in nociceptive sensitivity is likely to have some genetic basis using quantitative trait loci analysis to determine the substrates. Behavioural studies measure withdrawal thresholds; can be influenced by environmental factors and stress-induced antinociception. The end points can also influenced by sensory and motor pathways, motivation aspects and sedation. Furthermore, there can be substantial inter-experimenter variability in results obtained from behavioural studies 5. In contrast, in vivo electrophysiological dorsal horn neuronal recordings in mice allow both sub- and suprathreshold assessment - the latter possibly having more relevance to clinical pain issues. Electrophysiology is independent of many environmental factors and relatively independent of alterations to motor pathways and motivation etc. Inter-experimenter variability is greatly minimized, however anaesthesia effects must be considered.

From preliminary results, spinal cord neuronal responses of different mouse strains appear to resemble modality-specific traits observed behaviourally. Variation in modality-specific responsiveness of spinal neurones in response to peripheral natural stimuli may include differences in expression or coupling mechanisms of sensory receptors on primary afferent peripheral endings or differential central control of primary afferent terminals. Indication that central mechanisms may be of key importance in modality coding is the recent finding that variation in capsaicin sensitivity between mouse strains may be independent of TRPV genes 6 and our finding that descending controls markedly exert modality selective effects on central neurones 7. We plan to continue and complete characterization of dorsal horn neuronal responses in selected mouse strains as well as in a number of Pain Consortium generated knockouts (including tissue-specific), in collaboration with J. Wood. This will include use of models of neuropathy and inflammation. Work currently in progress involves mice lacking various sodium channels and a novel G-protein-coupled receptor. Electrophysiological characterization of the strain differences at the level of the spinal cord is important when comparing results obtained from studies using different mouse strains may and also when considering the impact of transgenic work. For example knocking out a receptor associated with thermal transduction in a mouse that is not very thermally sensitive may not be particularly useful. Furthermore transgenic mice are often produced on a mixed background and problems may arise when knockouts generated on mixed backgrounds of contrasting strain profiles display altered behaviour/neuronal responses that tend towards either inbred strain. Extending this work further and utilizing microarray technology available to the London Pain Consortium, in particular in conjunction with the Orengo lab, possible candidate receptors or channels providing a basis for the strain differences could be highlighted.

Ongoing research in our laboratory into receptors, channels and mediators involved in nociceptive pathways is undertaken in the more established rat models of neuropathy and inflammation, in which pharmacological studies utilizing in vivo spinal cord neuronal recordings are notably more stable. In vivo and in vitro projects investigating Cav2 voltage-dependent calcium channels, neuropathic pain states and novel blockers are currently in progress, extending previous studies 8, 9, and this may extend to encompass available transgenic mice.

1. Dickenson, A., E. Matthews, and R. Suzuki, Neurobiology of neuropathic pain: mode of action of anticonvulsants. European Journal of Pain, 2002. 6 51-60
2. Suzuki, R. and A.H. Dickenson, Neuropathic pain: nerves bursting with excitement. Neuroreport, 2000. 11 R17-21.
3. Matthews, E.A. and A.H. Dickenson, A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy. Anesthesiology, 2002. 96 633-40.
4. Lariviere, W.R. et al., Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain, 2002. 97 75-86.
5. Wilson, S.G. and J.S. Mogil, Measuring pain in the (knockout) mouse: big challenges in a small mammal. Behav Brain Res, 2001. 125 65-73.
6. Furuse, T. et al., Identification of QTLs for differential capsaicin sensitivity between mouse strains KJR and C57BL/6. Pain, 2003. 105 169-75.
7. Suzuki, R. et al., Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci, 2002. 5 1319-26.
8. Matthews, E.A. and A.H. Dickenson, Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy. Pain, 2001. 92 235-46.
9. Matthews, E.A. and A.H. Dickenson, Effects of ethosuximide, a T-type Ca(2+) channel blocker, on dorsal horn neuronal responses in rats. Eur J Pharmacol, 2001. 415 141-9.