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The London Pain Consortium making a difference
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.
www.imi.europa.eu.
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Ph.D. Positions
Specimen PhD projects
PhD projects to date

Rodent model of zoster-assocated pain.
Supervisors: Rice & Dickenson

Post-Herpetic Neuralgia (PHN) is one of the most common neuropathic pain syndromes, characterized by ongoing pain, varying degrees of sensory deficits, allodynia and hyperalgesia. It is a frequent complication of herpes zoster (HZ) with an increasing incidence that is directly related to age and has a devastating effect on quality of life for many patients that cannot be underestimated. However, PHN responds poorly to classical analgesics. This presents a need for the investigation of the mechanisms involved in the establishment of PHN and in the development of effective drugs for its treatment. An animal model of zoster-associated pain would increase our understanding of the pathophysiology of this condition and provide a pre-clinical screen for novel analgesic drugs. Behavioural paradigms will be taken beyond the simple reflex withdrawal paradigms conventionally employed in pain models to encompass spinal electrophysiological observations and measures of integrated pain behaviour, in addition to pharmacological validation. The association of viral infection with DRG gene correlates of neuropathic pain will also be investigated using a microarray approach.

Phenotypic characterization of lamina 1 neurons.
Supervisors: Hunt & Dickenson

A small population of lamina 1 neurons project to the parabrachial nucleus (Pb) and are important for nociception. The majority are NK1 positive. A reduction in response to peripheral noxious stimuli was observed when NK1 expressing neurons in lamina 1 was ablated. Lamina 1 ? Pb projection neurons also support LTP and are believed to modulate descending pathways to lamina 1. However little is known about the various types of proteins that are expressed in these projection neurons, and even less is known about the expression/modulation of proteins after noxious peripheral stimuli. In order to expand our knowledge in this field, lamina 1 ? Pb neurons will be studied using retrograde labelling techniques (from the Pb) using suitable tracers and by using in-situ or immunohistochemistry to reveal protein expression.

Cortical Pain Processing in Human Infants.
Supervisors Fitzgerald & Dickenson

Pain in infancy arises from disease processes, surgery or intensive care therapies. Infant pain measurements use indirect physiological methods but very little is known about information processing of noxious stimuli at cortical level in infants or fetuses. We propose to measure and map cerebral responses to noxious (clinical heel lancing) and non-noxious (touch and innocuous electrical) stimuli in preterm infants using near infrared spectroscopy (NIRS) and somatosensory event related potentials (SERP). In each infant the cerebral response will be compared with a standard assessment of pain behaviour (faces scale) to correlate behavioural outcome with cerebral activity. Using longitudinal and topographic measurements, we will study the maturation of these responses. This will improve our understanding of cortical pain processing in newborn infants undergoing intensive care.

Data Mining to Reveal Potentially Novel Genes and Biological Processes Involved in the Pain Response.
Supervisors Orengo & Koltzenberg

DNA microarrays are a new and promising biotechnology which allow the monitoring of expression levels in cells for thousands of genes simultaneously. To characterise the molecular events underlying neuropathy and its chronic pain, the London Pain Consortium is using microarrays to monitor expression of genes in the DRG and spinal cord tissues in animal pain models. It is the aim of this project to explore expression data generated by microarrays to investigate the molecular signature of neuropathic pain. Specifically, different approaches to clustering microarrays expression data aiming at grouping genes with similar expression pattern will be investigated and ultimately assessed using biological information. Functional annotation of the genes being studied will be a further aim to the project in order to make the validation of clustering efforts possible and provide clues to function of those genes relevant to the pathology being studies as identified by the analysis of microarray data. The project will also aim to build a database facility which will store descriptions of microarray experiments conducted by the consortium, the outcome of the datamining analysis as well as the functional annotation of genes of interest. A final target to the project will be to assess one of the technical limitations of microarray technology which consists of the limitation in the amount of extracted RNA. In this regard, amplifying RNA target for microarray profiling will be assessed.

The role of genetics and environment in pain.
Supervisors: McMahon & Koltzenburg

Assessing the role of genetic and environmental factors in the sensation of pain using a human psychophysical pain study on a large population of monozygotic and dizygotic twins. This is combined with genetic analysis and functional imaging to assess the inheritability of pain sensitivity. To complement this work, a cross fostering study on mice looking at baseline strain differences and the significance of uterine environment and postnatal rearing on the pain phenotype of the animal.

Functional properties of identified trigeminal primary afferents and adaptive changes following acute and chronic inflammation.
Supervisors: Koltzenburg & McMahon

There can be difficulty in obtaining satisfactory analgesia to allow dental treatment of acutely inflamed teeth following peripheral nerve block. This is clinically referred to as a ?hot pulp? and prevents ideal patient treatment in approximately one third of reported cases1. The reasons for this apparent failure of local anaesthetic is not fully understood. The trigeminal nerve is made up chiefly of sensory fibres innervating the various structures of the front of the head via the opthalmic, maxillary and mandibular divisions. The majority of neuronal cell bodies lie within the trigeminal ganglion and synapse with second order neurons within the brainstem. Although somatotopically organised the number of tissues innervated by this nerve has impeded detailed analysis. This project aims to test two hypotheses: (1) The functional properties of trigeminal primary sensory neurones are related to the target they innervate. (2) Trigeminal sensory neurones differ from dorsal root ganglion neurons in their functional properties and patterns of gene expression. The aims are to
? Identify subpopulations of trigeminal nociceptive neurons by retrograde labelling from target tissues including dental pulp, masseter muscle, facial skin and cornea using fluorescent markers
? Analyse changes during inflammation of target tissue using calcium imaging with application of nociceptive stimuli including capsaicin, cold, heat, eugenol, hyposmolarity etc.
? Create models of acute and chronic inflamed states and repeat above methods to assess difference in neuronal functional properties

NK-1 Receptors and Developing Pain Pathways.
Supervisors: Hunt and Fitzgerald

The aims of this project are to (i) characterize postnatal expression of NK-1 receptors in the dorsal horn of young and adult rats. (ii) investigate whether lamina I NK-1 expressing neurons and the parabrachial nuclei can be activated by noxious stimuli in the postnatal rat (iii) to investigate whether NK-1 has a role in mediating responses to acute and chronic responses to noxious stimuli in postnatal animals (iv) to assess the long term effects of ablation of dorsal horn NK-1 receptor expressing cells on the developing pain system.