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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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Archive workshop and seminar slides Professor Peter Karmerman…
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.
Current Research
The neural substrates of the association between neuropathic pain and negative affect
Neuropathic pain is often associated with debilitating emotional co-morbidities such as anxiety and depression. This project is part of a wider portfolio of animal and patient studies attempting to elucidate the link between neuropathic pain and affective disorders. This started with our recent work which demonstrated that correlates of such negative affect can be observed in a range of animal models of peripheral neuropathy. The aim of this project is to elucidate the neuroanatomical and biochemical basis of this link between neuropathic pain and negative affect at a brain level. A separate parallel project is investigating the role of spinal afferent pathways in driving these behaviours. Ultimately, we hope this strategy will reveal drug development strategies for novel treatments of these co-morbidities.
Our initial studies will target the amygdala as a key centre in neuropathic pain related anxiety. There is strong evidence of the involvement of the amygdala in the interactions between pain and emotion since it is one of the supraspinal centres involved in processing pain (it receives nociceptive inputs from the spinal cord, including via the parabrachial nucleus) and it is the centre that coordinates the motor, endocrine and vegetative components of the anxiety-fear responses (through its descending projections). Moreover, the amygdala is also involved in the emotional targeting of afferent stimuli (see Figure). Some innate aversive stimuli accede to the amygdala which generates emotional responses (fear/anxiety/aversion) against these stimuli. If there is a coincidence in the presentation of these innately aversive stimuli with neutral ones in the amygdala, a learned response can be generated and these former neutral stimuli can elicit, by themselves, an emotional response. Therefore, after the initial association, the neutral stimuli acquire a negative connotation and consequently, can provoke the negative experience. This system has a strong adaptive value since “predictor stimuli” allow us to avoid threatening situations, but if a perturbation in this system occurs, like those present in neuropathies where the nociceptive stimulus is always present, we can observe imbalances which lead to an over-expression of anxiety and therefore to an emotional dysfunction.
Our experimental approach will elucidate the role of discreet regions of the amygdala in driving the anxiety-like and depression-like behaviours which we have previously documented in animal models of neuropathic pain. Initially, we will employ stereotactic lesions of/microinjections into specific amygdaloid centres and determine the influence of such techniques in perturbing the expression of these behaviours in neuropathic rats. We will also study the activation of brain regions in neuropathic rodents by measuring the expression of c-Fos and related proteins and correlating this with the extent of affective behaviours observed in individual animals. Additionally, we intend to compare these animal findings with human functional brain imaging data from extensively phenotyped patients with peripheral neuropathies recruited from our clinics. Finally, we will perform gene microarray analysis of brain regions of interest (as revealed by the above approach) and then proceed to validate selected targets using a range of conventional biochemical and pharmacological approaches, as well as novel techniques available within the LPC such as RNA interference.

Background references:

(1) Hasnie FS et al. Further characterization of a rat model of varicella zoster virus-associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs. Neuroscience 2007;144(4):1495-508.

(2) Maratou K et al. Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain. Eur J Pain 2009;13 (387):398.

(3) Segerdahl AR et al. Fear-avoidance behaviour in rat models of neuropathic pain: 2 chamber light-dark box paradiagm. Soc.Neurosci.Abstr. 186.20. 2007.

(4) Wallace VCJ et al. The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy. Br J Pharmacol 2007;151(7):1117-28.

(5) Wallace VCJ et al. Anxiety-like behaviour is attenuated by gabapentin, morphine, diazepam in a rodent model of HIV anti-retroviral associated neuropathic pain. Neuroscience Letters 2008;448:153-156.

(6) Wallace VCJ et al. Characterisation of rodent models of HIV-gp120 and anti-retroviral associated neuropathic pain. Brain 2007;130(10):2688-702.

(7) Wallace VCJ et al. Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 2007;133(1-3):47-63.