Analysis Of Functional Role Of The BDNF Precursor In Sensory Neurons
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Neurotrophins, which are generated from their precursors, are essential for the survival and function of the nervous system. One of neurotrophins, brain derived neurotrophic factor (BDNF), is made in sensory neurons and transported towards nerve terminals. Mutation of a single amino acid in the precursor of BDNF disrupts this transport. This project will examine whether the precursor of BDNF has any function within sensory nerves. We will examine whether the precursor of BDNF gets into the nerve ....Neurotrophins, which are generated from their precursors, are essential for the survival and function of the nervous system. One of neurotrophins, brain derived neurotrophic factor (BDNF), is made in sensory neurons and transported towards nerve terminals. Mutation of a single amino acid in the precursor of BDNF disrupts this transport. This project will examine whether the precursor of BDNF has any function within sensory nerves. We will examine whether the precursor of BDNF gets into the nerve via its receptors and whether it plays any role in the development of pain and maintenance of neuropathic pain after nerve injury. Successful execution of the project will eludicate mechanisms of pain, especially neuropathic pain, and will provide important information to assist in the design of drugs for neurological diseases.Read moreRead less
Does The Complement System Contribute To Neuropathic Pain?
Funder
National Health and Medical Research Council
Funding Amount
$262,958.00
Summary
Nerve injury often results in increased sensitivity to painful stimuli and the perception of innocuous stimuli as painful; it may also result in spontaneous pain. These disorders of pain sensation due to nerve injury are common, debilitating and difficult to treat. They are symptoms of neuropathic pain. Pain is normally signalled to the brain by sensory nerve cells called nociceptors. Following nerve injury, nociceptors are sensitised by chemicals released by inflammatory cells. This contributes ....Nerve injury often results in increased sensitivity to painful stimuli and the perception of innocuous stimuli as painful; it may also result in spontaneous pain. These disorders of pain sensation due to nerve injury are common, debilitating and difficult to treat. They are symptoms of neuropathic pain. Pain is normally signalled to the brain by sensory nerve cells called nociceptors. Following nerve injury, nociceptors are sensitised by chemicals released by inflammatory cells. This contributes to neuropathic pain. We have evidence that inflammatory responses play a key role in initiating neuropathic pain. Other evidence suggests that the immune system contributes to neurological diseases and accompanying pain (e.g. Guillain-Barr syndrome and multiple sclerosis). We plan to test the idea that a component of the immune system known as the complement pathway contributes to the development of neuropathic pain following peripheral nerve injury. The outcome of this work will be a better understanding of the way in which nerve injury leads to chronic disorders of pain, including increased sensitivity to painful stimuli. This will lead in turn to the development of more effective treatments for neuropathic pain.Read moreRead less
Spinal Cord Injury Pain: Understanding Mechanisms To Develop Treatments
Funder
National Health and Medical Research Council
Funding Amount
$597,675.00
Summary
Spinal cord injury has devastating effects on health and quality of life. Many of the major consequences of injury, such as chronic pain and loss of voluntary voiding, are "invisible" – i.e., they are not as visible as limitations of mobility. Our study aims to define the neurobiological changes that cause development of persistent pain after spinal cord injury and use pharmacological tools to attenuate the development of pain.
Understanding The Role Of Regulatory T Cells In Chronic Pain Following Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$587,046.00
Summary
Neuropathic pain is a debilitating condition of chronic pain that develops after damage to the nervous system, and lacks an effective treatment. This project focuses on the novel hypothesis that the immunosupressive regulatory T cells and their mediators play a critical role in controlling neuroinflammation and pain hypersensitivity following peripheral nerve injury. This study promises to enhance our understanding of the neuroimmune activation in neuropathic pain and offers novel approaches for ....Neuropathic pain is a debilitating condition of chronic pain that develops after damage to the nervous system, and lacks an effective treatment. This project focuses on the novel hypothesis that the immunosupressive regulatory T cells and their mediators play a critical role in controlling neuroinflammation and pain hypersensitivity following peripheral nerve injury. This study promises to enhance our understanding of the neuroimmune activation in neuropathic pain and offers novel approaches for pain management.Read moreRead less
Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones receive and process pain-signalling information from the skin ....Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones receive and process pain-signalling information from the skin and internal organs, and receive inputs from descending pathways. This descending input can either inhibit or enhance the activity of SDH neurones and subsequent pain perception. Till now it has been difficult to directly examine how descending pain pathways influence the small SDH neurones in the spinal cord. A new approach, which has been developed in our laboratory, now allows us to record from these very small SDH neurones in the spinal cord of an intact deeply anaesthetized mouse. In addition, our technique allows us to examine the recorded SDH neurone s responses to functionally relevant stimuli (brushing or pinching the hindpaw) as well as its physiology and anatomy. This project will use our new techniques to examine the effects of activating descending brainstem pathways that alter the way painful stimuli are processed in the spinal cord. The effects of altered levels of inhibition in the spinal cord will also be studied by using mice with naturally occurring mutations in their inhibitory glycine receptors. We believe a more complete understanding of pain processing mechanisms will be achieved by examining the role of descending pathways in an intact animal preparation. Such data are essential for the development of drug therapies that can successfully target pain syndromes.Read moreRead less
Pain Systems Analysis Highlights PI3K Gamma As A Candidate Regulator Of Nociception.
Funder
National Health and Medical Research Council
Funding Amount
$461,810.00
Summary
Chronic pain will affect most of us at one point in our life, and there is a need for new drugs to manage this condition. The goal of this project is to use our computer modeling of genetic data from multiple species to predict new drug targets, and then use mouse models to look at the mechanism of action for predicted drug targets, and validate one potential drug target in particular for its therapeutic abilities to stop chronic pain.
Targeting GDNF Family Ligand (GFL) Signalling To Treat Inflammatory Bone Pain
Funder
National Health and Medical Research Council
Funding Amount
$329,285.00
Summary
Pain associated with bone marrow oedema syndromes, osteomyelitis, osteoarthritis, fractures and bone cancer causes a major burden on individuals and health care systems in Australia and worldwide. In this application, we will explore specific signalling pathways that we have identified in nerves that code bone pain. This will provide an opportunity for the rational design of highly specific drugs capable of interacting exclusively with molecules that drive pain in these conditions.
Discovery And Development Of Better Pain Treatments
Funder
National Health and Medical Research Council
Funding Amount
$9,613,850.00
Summary
Many forms of pain remain poorly treated, leading to significant quality of life and economic losses. This Program grant will discover and characterise new peptides from cone snails and spiders that modulate specific channels in nerves that are critical to the transmission of pain signals to the brain. Using advanced chemical and structural approaches, promising leads will be optimised for potency and stability and evaluated in disease and pathway-specific models of pain to establish their clini ....Many forms of pain remain poorly treated, leading to significant quality of life and economic losses. This Program grant will discover and characterise new peptides from cone snails and spiders that modulate specific channels in nerves that are critical to the transmission of pain signals to the brain. Using advanced chemical and structural approaches, promising leads will be optimised for potency and stability and evaluated in disease and pathway-specific models of pain to establish their clinical potential.Read moreRead less
THE AUTONOMIC, SOMATIC AND CENTRAL NEURAL RESPONSES TO DEEP AND SUPERFICIAL PAIN IN HUMAN SUBJECTS
Funder
National Health and Medical Research Council
Funding Amount
$375,750.00
Summary
Pain is a subjective experience, the intensity of which can be readily influenced by personal experience. Despite this, pain originating from a particular part of the body will usually be described by all individuals as having similar character. For example, pain arising from the skin is commonly described as being sharp or burning and is usually easy to localise, whereas pain arising from muscle is commonly dull, throbbing and diffuse. In addition to producing sensory changes, pain also evokes ....Pain is a subjective experience, the intensity of which can be readily influenced by personal experience. Despite this, pain originating from a particular part of the body will usually be described by all individuals as having similar character. For example, pain arising from the skin is commonly described as being sharp or burning and is usually easy to localise, whereas pain arising from muscle is commonly dull, throbbing and diffuse. In addition to producing sensory changes, pain also evokes changes in blood pressure, heart rate and motor activity (often in an attempt to remove the source of the pain). The proposed research aims to characterise the cardiovascular and motor patterns associated with pain originating in skin and in muscle and to examine the brain regions that produce these changes. More specifically, microelectrodes will be used to investigate changes in peripheral nerve activity during transient painful skin and muscle events in awake human subjects. In a separate investigation functional magnetic resonance imaging will be used to determine brain sites that are activated by skin or muscle pain.Read moreRead less
Piezo2 And Pain - Is There A Role For Piezo2 In Mechanically Induced Bone Pain?
Funder
National Health and Medical Research Council
Funding Amount
$543,848.00
Summary
Pain associated with bone marrow edema, osteoarthritis, bone cancer and fracture puts a significant burden on individuals, society, and the health care system in Australia. A dominant feature of these includes mechanical disturbances of the bone, and this is a trigger for the pain. In this study, we will determine if a newly discovered mechanically gated ion channel (Piezo2) is a key contributor to mechanically induced bone pain and could be a target for development of drugs to treat it.