Do pain mechanisms and levels of central sensitisation predict effective self-management in patients with Chronic Low Back Pain?
Pain mechanisms and levels of central sensitisation reflect changes in the central nervous system and pain processing which may impact on the ability of patients to effectively cope and manage their pain effectively. Identification of these factors may allow early targeted management for these patients. As central sensitisation is not present on all patients suffering from a chronic musculoskeletal condition, efficient stratification must be followed to examine in detail the effectiveness of self-management. From an extended scope, the findings of the project might influence self-management procedures in other chronic pain states such as fibromyalgia, whiplash, chronic neck pain etc. as pain mechanisms function in the same way and central sensitisation follows similar patterns regardless of the condition.
Alterations in neurovascular barriers in response to chronic pain states across post-natal development
Multiple pain states are known to have an impact on the functioning of neurovascular barriers such as the blood brain barrier (BBB), blood spinal cord barrier (BSCB), and blood nerve barrier (BNB). These barriers are pivotal in controlling entry of potentially neurotoxic molecules and cells into the CNS and neural parenchyma, but under neuropathic and inflammatory conditions, barrier integrity can become compromised and allow infiltration of non-neuronal cells. This project aims to monitor the integrity of neurovascular barriers in response to nerve injury and inflammation, and to determine whether these responses differ with age.
Immunological contributions to age-dependent variations in response to cutaneous inflammation and the programming of later life pain
Pain pathways mature over the first weeks and months of life in rodents, and years in humans. In early life, thresholds to painful stimuli are lowered and behavioural responses to noxious stimuli are altered. Previous work has demonstrated that inflammatory stimulus leads to different nociceptive responses in the early life, compared with adulthood.
My research aims to characterise the ability of various inflammatory stimuli to prime the nociceptive pathways in early life, and identify key differences in immunological and pain responses between neonates and adults. Furthermore, we will determine the impact this has on the response of the nociceptive system to re-exposure to inflammatory signals later in life. This project will use a range of in vivo and in vitro approaches to compare inflammatory processes in response to single and repeat inflammation in cutaneous tissue at different postnatal ages in rats. Techniques including FACS analysis, immunohistochemistry linked to fluorescence microscopy and pain behaviour assays will be utilised. We will also perform quantification of alterations in the expression of key genes involved in inflammatory processing in isolated inflammatory cells.
A clinical assessment tool to improve the use of pain relieving treatments in knee osteoarthritis
Phenotypes found to contribute to knee osteoarthritis (OA) pain via peripheral mechanisms and central mechanisms were used in the development of the questionnaire items. Items which discriminate between peripheral and central mechanisms of knee OA pain will be explored in order to develop a validated and reliable short clinical tool (which will include questions and, possibly, additional simple aspects of clinical assessment). Patient completed questionnaires will be considered for factor analysis to determine effective mechanism based stratification in patients.
Role of prostaglandins in the periaqueductal gray in the central modulation of osteoarthritis pain
The experience of pain in osteoarthritis (OA) is significantly affected by central pathways of pain modulation, where the midbrain periaqueductal gray (PAG) is known to play a crucial role through central sensitization and hyperalgesia. Prostaglandins (PGs) enhance nociceptive transmission both peripherally and centrally, and have been recognized as mediators of PAG-facilitated modulation of pain.
This study aims to look into the role of PGs in the PAG in the descending facilitation of nociception in OA using the monoiodoacetate (MIA) model, as well as the complete Freud's adjuvant (CFA) model of inflammatory arthritis, and conduct a comparison between the two models. Techniques such as PCR, immunofluorescence and electromyography (EMG) recording will be used in this project.
Nuria Casanova Vallve
The time-course of development of muscle wasting and insulin resistance in a rodent pain model of osteoarthritis.
The purpose of this study is to advance understanding of the relationship between pain and muscle function in knee OA and the contribution of changes in metabolism to OA pain, inflammation and muscle disuse. This will be achieved by determining longitudinal changes in muscle metabolism in well characterised rodent models of OA pain, and undertaking intervention studies to confirm the nature of associations between these clinical relevant features of OA. Identification of the changes in muscle carbohydrate oxidation associated with molecular signalling pathways leading to muscle atrophy will allow us to understand the role of a complex variation of factors involved in OA. It will be able to help future studies to identify better treatments for people living with OA.
Postnatal neurophysiological development of nociception: integration and representation into supraspinal networks
My project aims to understand fundamental physiological aspects of chronic pain by understanding how both the spinal cord and brain respond and adapt to it. This will be done using a model of arthritis so that any discoveries made are relevant to many people who are in pain. The techniques that this project will develop should provide a framework for further comprehensive work to be done that may be more relevant in a clinical setting. Furthermore, this project is particularly interested in how the pathways and networks that are relevant to chronic pain develop in adolescence. Significant work will be done to measure and understand how neural nociceptive-evoked activity changes over development.
Relative efficacy of different types of exercises in the treatment of knee osteoarthritis – a network meta-analysis of randomised controlled trials
Investigations of the origins of altered pain perception in a commercial pig strain
This project will examine the relationship between degenerative joint disease (osteoarthritis) and pain in commercial breeder pigs. Pain behaviours will be evaluated in commercial pigs and the relationship to joint disorders evaluated by assessing joint chondropathy, changes in the phenotype of sensory nerves innervating the affected joint, changes in the spinal cord and changes in the synovium and synovial fluid. The results found in pigs will then be compared to a well validated rodent model of osteoarthritis pain, with a secondary aim of the project to evaluate pig joint disease as a model of human osteoarthritis.
Relative efficacy of topical NSAIDs and topical capsaicin in osteoarthritis and neuropathic pain
The project aims to better understand the mechanism of pain in osteoarthritis. It will aim to do so by identifying treatment responders, making comparisons between treatments with different mechanisms of action, and between osteoarthritic and neuropathic pain. Conventional, network, and individual patient data meta-analyses of randomised controlled trials evaluating the efficacy of topical NSAIDs and topical capsaicin in osteoarthritis will be conducted. The relative efficacy of both treatments will be assessed in osteoarthritis, and treatment responders will be identified. Comparisons will be made with randomised controlled trials of neuropathic pain.
Targeting the resolution of inflammation to reduce spinal excitability and pain
Resolvins are endogenous lipid mediators derived from docosahexaenoic acid (DHA, D-series) and eicosapentaenoic acid (EPA, E-series) that exhibit potent anti-inflammatory and pro-resolving properties. One of these products, known as aspirin triggered resolvin D1 (AT-RvD1), has robust analgesic lead compound for the treatment of pain from different origins, focusing on potential spinal mechanisms of action. I have demonstrated inhibitory effects of spinal AT-RvD1 in a model of acute inflammatory pain, but this effect is lost in a model of osteoarthritis pain. An ongoing study will evaluate its effects in a model of chemotherapy-induced peripheral neuropathic pain. Further studies will investigate the underlying mechanisms that lead to the differential inhibition of spinal nociceptive processing by AT-RvD1 in models of acute versus chronic pain.
Translational studies of central sensitization in the rat monosodium iodoacetate model of osteoarthritis pain
This project will use pre-clinical animal models of knee osteoarthritis (OA) to investigate the effects of chronic pain on descending inhibitory controls by looking at how diffuse noxious inhibitory controls (DNIC) modulate spinal nociceptive reflexes. DNIC can be evoked by applying a noxious stimulus to widespread areas of the body outside the peripheral excitatory receptive field of the reflex and previous studies have shown that dysfunction in these inhibitory pain pathways may be a key contributor to chronic pain. By investigating whether DNIC is altered in OA and the mechanisms underlying these alterations, we hope to increase our understanding of pain mechanisms during OA.
Dates: Apr 10 - Mar 2014
Supervisor: Dr R Dineen
Hamza was appointed to investigate the structural brain changes associated with chronic pain of knee osteoarthritis. Up-to-date structural image analysis tools were used to quantitatively analyse high-resolution brain images obtained using advanced MRI scanning techniques
Dates: Jan 11 - Dec 14
Supervisor: Dr A Bennett
Osteoclasts have an important role in bone remodelling and have been shown to contribute to bone cancer induced pain. Both clinical and preclinical evidence supports a role of osteoclasts in osteoarthritis, which is associated with bone remodelling and chronic pain. This project investigated the signalling pathways which mediate osteoclastogenesis using a combination of molecular biology, primary cell culture, mass spectrometry and fluorescence imaging techniques. The potential interactions of these signalling pathways with peripheral pain mechanisms were assessed in models of osteoarthritic pain.
Dates: Nov 11 - Oct 14
Supervisor: Dr W Zhang
The project investigated the placebo effect in fibromyalgia and its potential determinants in randomized controlled trials. Meta-analysis was used to summarise the placebo and nocebo effects for different types of placebos. The effect sizes were compared between fibromyalgia and osteoarthritis. The duration of the placebo effect and associated factors were examined.
Dates: Sept 11 - Jul 14
Supervisor: Prof V Chapman
The contribution of peripheral and central inflammatory responses to pain responses associated with osteoarthritis (OA) will be studied in models of OA pain. Techniques will include behavioural studies of pain responses and ex vivo analysis of tissues from these models. Immunohistochemistry, western blotting and RT-PCR will be used to investigate expression levels of receptors, cytokines and other pro- and anti-inflammatory mediators in these models of OA pain
Luting Xu (Tracey)
Dates: Oct 10 - Sept 14
Luting (Tracey) focused on elucidating the mechanism underlying the formation of osteoclast in OA and how it was associated with OA pain. Molecular biology, gene expression analysis and cytohisochemistry techniques were employed. The PhD programme focusses on the TRPV1 signaling pathway, modulation by lipid metabolism and its relationship with pathological bone remodeling in osteoarthritic joints
Dates: Oct 11 - Jul 14
Kun undertook a project to examine the relative effect of placebo (contextual effect) in complementary therapy in osteoarthritis (OA). The PhD project investigated the effect size of the contextual effect for each complimentary treatment modality. Comparisons were made between treatments, as well as between OA and other chronic painful conditions (fibromyalgia and rheumatoid arthritis). Meta-analysis was used to combine results and different treatment categories and determinants of the contextual effect and related adverse events (nocebo effects) were also examined
Dates: Oct 11 - Oct 15
Supervisor: Prof D Walsh
Laura Wyatt (nee Stoppiello)
A comparison of structural and biochemical factors in joint tissues from knees of patients undergoing joint replacement surgery for OA pain with those with similar degrees of chondropathy that have been obtained post mortem from people who have not sought help for knee pain. The development of key structural and biochemical changes with OA disease progression will be determined by comparing human tissues to OA models. Knee joint structural and biochemical changes predicting pain phenotype will be explored. Finally, one key molecular or structural target emerging from these studies will be tested in interventional studies in an appropriately validated model.
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