Investigation postnatal changes in the connectivity and physiological role of the periaqueductal grey and how this affects descending pain pathways - Emma Battell
Gene expression analysis and Risk of gout: a case-control study - Gabriela Sandoval-Plata
Development of an optimal non-pharmacological treatment package for fibromyalgia - Burak Kundakci
Investigation postnatal changes in the connectivity and physiological role of the periaqueductal grey and how this affects descending pain pathways
Supraspinal centres serve critical roles in producing behavioral responses to pain and modulating the excitability of spinal pain networks. This descending pain modulation system (DPMS) comprises several centres in the brain with the periaqueductal grey (PAG) serving as an integrative centre. The PAG hassignificant afferent input from the forebrain and limbic system and an efferent projection to the brainstem.
Significant postnatal changes occur in the PAG and brainstem that profoundly effect sensory processing. This project aims to detail changes in the function and connectivity of the PAG across postnatal development.
Epidemiology of Osteoarthritis and it’s comorbidities
Osteoarthritis (OA) is one of the common chronic conditions in older people and often causes chronic joint pain and disability. Despite the rise in multimorbidity there is little information available on the proportion of people with OA have multiple chronic conditions and how it changes with time. According to a recent research, three out of ten people in the UK have more than at least one long term condition. However, the pattern and association of these conditions with OA is not well understood.
This research aims to use advanced statistical techniques to understand the epidemiology of OA in the UK and multiple chronic conditions associated with. Furthermore, the risk, burden and impact of multiple chronic conditions in OA will be studied in detail.
Commenced: 1 October 2018 Supervisors: Abhishek Abhishek and Kevin Morgan
Gene expression analysis and Risk of gout: a case-control study
Gout is one of the most common forms of inflammatory arthritis, with a prevalence of 2.49% in the UK. It is characterised by abrupt episodes of acute inflammation and severe pain in joints due to monosodium urate (MSU) crystals deposition as a consequence of hyperuricemia. Despite being crucial to gout, hyperuricemia does not necessarily cause the disease, but the reasons underlying the progress from asymptomatic crystal deposition in people with hyperuricemia to gout remains unclear. Moreover, clinical variation among patients with gout in terms of the age of onset, frequency of attacks and the development of tophi is still poorly understood.
Based on the fundamental role of the NLRP3 inflammasome and toll-like receptors (TLR) pathway in the immune response to MSU crystals, the aims of the present project is to analyse gene expression of inflammasome and TLR-related genes to: (1) evaluate if it is influenced by serum uric acid levels, (2) evaluate whether a differential expression is associated to the development of symptomatic gout, and (3) explore the expression profile during acute and intercritical gout. In addition, polygenic risk models will be developed to distinguish gout cases vs controls, and to determine risk for gout in people with hyperuricaemia who has not developed gout.
Developing and evaluating the feasibility of a nurse-led complex package of care for knee pain.
Knee OA manifests clinically with pain, stiffness and disability. Knee pain is a common problem, with 25% of the population older than 55 years in age having persistent knee pain and knee pain present on most days of the previous month, is present in one in five adults over the age of 40 years.
National Institute for Health and Care Excellence (NICE) have recommended core, adjunctive non-pharmacological and pharmacological treatments for OA. However, core treatments suggested by NICE are under-utilised as both doctors and patients often focus predominantly on pharmacological systemic analgesics alone. Doctors do not appear to be best suited for managing knee pain due to OA. Even enhanced GP consultations based on an OA guidebook followed by referral to a practice nurse-led OA clinic and provision of a written information on OA did not improve several quality indicators for knee OA.
The overall purpose of the study is to test the feasibility of conducting a RCT of a nurse-led complex intervention comprising education, non-pharmacological and pharmacological principles of management of OA and knee pain.
Individualised exercise intervention for hip and knee osteoarthritis
Khalid is doing a systematic review, Delphi study and feasibility study to develop optimal individualisation methods for exercise to treat osteoarthritis.
Identifying key elements of non-pharmacological treatment package for fibromyalgia: Evidence synthesis and Delphi exercise
Fibromyalgia (FM) is a common chronic condition that manifests with chronic widespread pain or multiple regional pain, and with other associated core symptoms of fatigue, non-restorative sleep and cognitive dysfunction. After osteoarthritis, FM is the second most common rheumatologic condition, and affects 2-8% of the whole population. Universally guidelines on the management of FM support a multi-faceted approach combining non-pharmacological interventions as first-line therapy and pharmacological interventions as adjunctive treatment, with an emphasis on an individualised patient-centred approach.
The overall purpose of the research project is the development of an optimal non-pharmacological treatment package for FM. It primarily aims to estimate the efficacy and relative efficacy of all non-pharmacological interventions, select the most efficacious, accessible and applicable interventions and bring them together as a package of care. Firstly, studies comparing a non-pharmacological intervention versus a non-intervention will be used to calculate overall effect sizes for each non-pharmacological treatment by conducting a conventional meta-analysis. Secondly, these treatments will be prioritised by Network Meta-Analysis using direct and indirect evidence. Finally, a Delphi exercise (consensus building) will be undertaken among patients and healthcare professionals to select the most effective and accessible interventions.
Digital Exercise Intervention for Knee OA – Link between sleep and pain relief
Knee osteoarthritis is a most common form of arthritis in the world. In the United Kingdom, 10% of 65-74-year-old individuals consult their general practitioners about osteoarthritis per year. Knee arthritis is a significant issue in the elderly population, therefore, a cheaper community-based intervention approach will be beneficial for both these patients and the NHS.
The aim of this study is to explore the benefits of web-based physical exercises in the patients with knee osteoarthritis to establish if their pain decreases after six weeks of intervention. We will be using a web-based exercise platform known as Joint Academy. Participants in the intervention group will be asked to log in and practice knee exercises for 30 minutes daily. We will assess their sleep patterns using actigraphy; pain detection levels by quantitative sensory testing; and signs of inflammation and muscle mass using musculoskeletal ultrasound, in addition to completing standardised pain and sleep questionnaires.
Studying these parameters will help us to understand the traits of osteoarthritis, their correlation to each other and potential detrimental effects of them on the health of knee joint.
Understanding the role of messenger RNA regulation in pain nerves during osteoathritis
Hyperalgesia is a recognised feature of osteoarthritis which is at least in part due to changes in nociceptor neurons that innervate the joint. Regulation of local protein synthesis by mRNA localisation and cytoplasmic polyadenylation have recently been implicated in nociceptor plasticity. It has been shown that the polyadenylation inhibitor cordycepin affects pain behaviour in rodent models of osteoarthritis (OA). This project will aim to increase our knowledge of which mRNAs are localised and polyadenylated in nociceptor neurons and their role in hyperalgesia. Advanced gene therapy techniques will be utilised to evaluate the role of polyadenylation in regulating protein synthesis of specific mRNAs in axons of pain nerves in cell culture systems as well as a mouse model of OA.
The Differential Roles of Vascular Endothelial Growth Factor Isoforms in the Context of Chronic Pain and Peripheral Neuropathy
Chronic pain is a major worldwide health burden with an asymmetry between prevalence and effective treatments. Additionally, chemotherapy induced peripheral neuropathy (CIPN) is emerging as a major contributor to the aforementioned burden, and a limiting factor in the supply of chemotherapy regimens. Thus, there is a large demand for the rapid development of novel analgesic drugs with which to counter the growing requirement for efficacious therapeutics.
One such approach is modulation of Vascular Endothelial Growth Factor (VEGF) synthesis. Differentisoforms of VEGF have profound neuroprotective and anti-nociceptive functions. Therefore, my project is centred on developing a series of potential therapeutics that would initiate synthesis of these VEGF isoforms over those that normally predominate in pain states. This provides a new and innovative approach to pain management therapy.
Developmental changes in neural stem cell responses in the spinal cord and the influence of painful stimulation
Neural stem cells (NSCs) are highly proliferative cells that play a fundamental role in the generation of glial cells and neurones in the developing CNS. There are high numbers of NSCs in the CNS throughout development, however in adulthood they become confined to specific regions including the central canal of the spinal cord. The role of NSCs has been explored following adult spinal cord injury but whether they play a role in the spinal processing of pain is yet to be investigated. This project aims to investigate NSC expression in the spinal cord throughout normal postnatal development and identify whether there are changes in NSC responses following painful stimulation both in early life and adulthood.
Peripheral contributions to the developing and maintenance of chronic pain in osteoarthritis in the knee joints
Practically I will aim to understand how pain progresses during the disease specifically in the peripheral nervous system in conjunction with the signalling to the CNS.
Moreover, given the inconsistency of the drugs that currently exist against OA, I will focus my research on understanding the basic mechanisms of VEGFA isoforms when used against OA, since there are evidence that targeting VEFGA can reduce pain. However the question of what happens to the inflammation still stands. Moving forward in the next steps of the PhD I will try to tackle the question of how inflammation progresses and alters in conjuction to pain.
A link between chronic pain and anxiety
Incidence of anxiety disorders among chronic pain patients is disproportionately higher than in general population. Anxious pain patients are characterized by decreased pain thresholds, increased pain levels, more daily complaints, poorer quality of life and worse outcome of treatment. Underlying mechanisms of negative influence of anxiety on pain are still poorly understood.
The main aim of my research is to understand neural mechanisms of coexistence of two disorders and to suggest new methods of treatment and management of chronic pain conditions with co-morbid anxiety.
Mechanistic studies of the impact of chronic pain on brain, behaviour and cognition in rat models of osteoarthritis
This project aims to determine how chronic osteoarthritis (OA) pain affects two important everyday cognitive functions, memory and attention, by combining methods from pain research and behavioural and integrative neuroscience. The monoiodoacetate (MIA) model of knee OA in rats will be used to examine the impact on hippocampus-dependent memory and prefrontal-dependent attention, using the watermaze DMP and the 5CSRT tests, respectively. Furthermore, we will characterise changes within these key brain regions.
Mechanistic studies of the transition from acute to chronic pain in osteoarthritis models
This project will examine the central and peripheral mechanisms involved in mediating the transition from acute to chronic pain in clinically-relevant animal models of osteoarthritis. These mechanisms will be investigated using both in vivo and ex vivo techniques, including single-unit spinal electrophysiology. Currently, changes in GABAergic signalling in the MIA model of OA pain are being explored using both agonists and antagonists of the GABAA receptor.
Age-related Changes in the Phenotype of Spinal Microglia
Microglia play a central role in immune surveillance and modulation of neuroinflammation as well as playing a role in neurodevelopment. Microglia play a crucial role in the development of pathological pain in adults but not early in life however little detail is known about the changing phenotype of spinal microglia during development. This project aims to understand the age-related changes in spinal microglia following activation with pathogen- and damage- associated molecular patterns. This will be done by preparing microglial cultures from neonatal postnatal day (P) 1 adult (P40) rat spinal cords. Furthermore, this project is particularly interested in investigating the role of nuclear receptor Nr4a2 in modulating the microglial cells in neuroinflammation. Techniques including phagocytosis and nitric oxide production assays, and immunocytochemistry will be employed. We will also perform quantitative assessment (qPCR) of expression levels of key inflammatory genes in isolated microglial cells.
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 the central gliovascular barrier in response to inflammatory pain
Multiple pain states are known to have an impact on the functioning of gliovascular barriers such as the blood brain barrier (BBB) and blood spinal cord barrier (BSCB). These barriers are pivotal in controlling entry of potentially neurotoxic molecules and cells into the CNS and neural parenchyma, but under inflammatory conditions, barrier integrity can become compromised to allow infiltration of non-neuronal cells and can lead to glial cell alterations. This project aims to monitor the gliovascular alterations in response to peripheral inflammation, and to investigate the role of VEGFR2 in these changes.
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.
Relative efficacy of different types of exercises in the treatment of knee osteoarthritis – a network meta-analysis of randomised controlled trials
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: April 2010 - Mar 2014
Supervisor: 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: January 2011 - December 2014
Supervisor: 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: November 2011 - October 2014
Supervisor: 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: September 2011 - July 2014
Supervisor: 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: October 2010 - Sept 2014
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: October 2011 - July 2014
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: October 2011 - October 2015
Supervisor: 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.
Dates: January 2015 - May 2018
Supervisor: G Hathway
Postnatal neurophysiological development of nociception: integration and representation into supraspinal networks
My project aimed to understand fundamental physiological aspects of chronic pain by understanding how both the spinal cord and brain respond and adapt to it. This was 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 developed should provide a framework for further comprehensive work to be done that may be more relevant in a clinical setting. Furthermore, this project was particularly interested in how the pathways and networks that are relevant to chronic pain develop in adolescence. Significant work was done to measure and understand how neural nociceptive-evoked activity changes over development.
Dates: April 2014 - March 2018
Supervisor: L Donaldson
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.
Meesawatsom Pongsatorn (Den)
Dates: October 2013 - September 2017
Nuria Casanova Vallve
Dates: January 2015 - September 2019
Supervisor: Victoria Chapman
Dates: May 2015 - September 2019
Supervisors: John Harris and Carl Stevenson
Investigations of the origins of altered pain perception in a commercial pig strain
This project examined the relationship between degenerative joint disease (osteoarthritis) and pain in commercial breeder pigs. Pain behaviours were 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 were then 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.
Dates: October 2015 - September 2019
Supervisors: Weiya Zhang
Relative efficacy of topical NSAIDs and topical capsaicin in osteoarthritis and neuropathic pain
The project aimed to better understand the mechanism of pain in osteoarthritis. It did 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 were conducted. The relative efficacy of both treatments was assessed in osteoarthritis, and treatment responders was identified. Comparisons were made with randomised controlled trials of neuropathic pain.
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