Mechanisms Of Endogenous Cannabinoid Mediated Analgesia Within The Midbrain
Funder
National Health and Medical Research Council
Funding Amount
$518,820.00
Summary
While opioid analgesics such as morphine are the most important drugs used to treat moderate to severe pain, their usefulness is limited by side effects such as tolerance and respiratory depression. In addition, clinically relevant neuropathic chronic pain syndromes (caused by nervous system damage) are relatively resistant to opioids. Animal studies have shown that the active ingredient of the plant Cannabis sativa, THC, and a number of synthetic cannabinoids are analgesic in acute pain models, ....While opioid analgesics such as morphine are the most important drugs used to treat moderate to severe pain, their usefulness is limited by side effects such as tolerance and respiratory depression. In addition, clinically relevant neuropathic chronic pain syndromes (caused by nervous system damage) are relatively resistant to opioids. Animal studies have shown that the active ingredient of the plant Cannabis sativa, THC, and a number of synthetic cannabinoids are analgesic in acute pain models, and interestingly, in chronic neuropathic pain models. Unfortunately, cannabinoid also produce a spectrum of adverse side-effects. Administered cannabinoids such as THC produce their physiological effects by mimicking the actions of the body's own cannabinoids (endocannabinoids) by activating cell-surface proteins, called cannabinoid receptors. The endocannabinoid neurotransmitter system is emerging as a potential therapeutic target. For example, it has recently been shown that analgesia induced by physiological stressors is partly mediated by endocannabinoids within the brain. In addition, novel endocannabinoid breakdown inhibitors have some efficacy in animal models of anxiety and chronic pain. Several brain regions are known to play a pivotal role in the analgesic actions of exogenous and endogenous cannabinoids. In previous studies I have identified the cellular mechanisms by which exogenously applied opioids and cannabinoids produce their analgesic effects in single brain cells. However, the mechanisms of endocannabinoid actions within these brain regions are unknown. The proposed study will determine the cellular actions of endogenously released cannabinoids in normal animals and in chronic pain states. Parallel studies will examine the effect of modulation of the endocannabinoid system in animal models of pain. These techniques have the potential to identify novel endocannabinoid analgesic pharmacotherapies with enhanced efficacy and reduced side effects.Read moreRead less
I am a clinical scientist translating basic science findings into clinical science questions and answers that impart better understanding and management of pain and painful disease.
Mechanisms Of Serotonergic And Triptan Mediated Analgesia Within The Midbrain
Funder
National Health and Medical Research Council
Funding Amount
$546,937.00
Summary
Chronic pain requires multiple pharmacological interventions and these are often ineffective. These drugs include those which act on a diverse group of cell-surface proteins, called serotonin receptors. This project will use cellular and whole animal techniques to examine how these agents act within intrinsic pain and anxiety control systems within the brain in order to identify novel analgesic pharmacotherapies with enhanced efficacy and reduced side effects.
Stimulus Induced Synaptic Plasticity In The Amygdala
Funder
National Health and Medical Research Council
Funding Amount
$428,777.00
Summary
Acute pain provides important warnings about dangers in our environment. However some clinical conditions produce chronic-persistent pain that outlasts the original injury and its useful role. This persistent pain is a debilitating condition that affects 20% of the Australian population and is characterized by painful sensory experience and a negative emotional state. The clinical management of persistent pain remains problematic due to the intolerable side effects associated with the escalating ....Acute pain provides important warnings about dangers in our environment. However some clinical conditions produce chronic-persistent pain that outlasts the original injury and its useful role. This persistent pain is a debilitating condition that affects 20% of the Australian population and is characterized by painful sensory experience and a negative emotional state. The clinical management of persistent pain remains problematic due to the intolerable side effects associated with the escalating doses required for adequate pain relief and the limited efficacy of current drug therapies in some clinically important pains states. The persistence of pain after the original injury has resolved suggest the development of adaptations that result in the ongoing pain. The changes in neurobiology underlying persistent pain are poorly defined. A better understanding of this neurobiology will result in better therapeutic approaches to persistent pain. The amygdala is a brain region that is important for pain processing, endogenous analgesia and emotion. A neuronal pathway that delivers information about pain to the amygdala has recently been shown to be critical for the development of persistent pain. Little is known about whether this critical neuronal pathway is modified by pain. This project will determine using electrical and chemical techniques how a brief or persistent painful stimulus changes the delivery of painful information to the neurons in the amygdala. The changes produced by a brief painful stimulus likely represent the initial changes in the development of a persistent pain state. This information may allow us to more fully understand the transition from acute to persistent pain and the changes defined may be sensitive to pharmacological modulation. Preventing or inhibiting these pain induced changes may provide better treatment for persistent pain or ideally prevent people undergoing the transition from acute to persistent pain.Read moreRead less
Physiological Mechanisms Of Efficacy Of Cervical Flexor Muscle Retraining
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain, probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing and relieving pain and improving the neck function. Currently there are several, quite different methods of exercise and there is controversy regarding how therap ....Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain, probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing and relieving pain and improving the neck function. Currently there are several, quite different methods of exercise and there is controversy regarding how therapeutic exercise works. It has been argued that parameters such as changes in muscle strength, endurance, joint position sense or muscle coordination may be responsible for the clinical efficacy. It is difficult to disentangle the effective component of exercise strategies and thus prescribe the most effective exercise strategies. This series of experiments will evaluate the physiological factors that change with a specific exercise intervention and to compare different exercise modalities in order to identify the most effective means to induce these changes. Cervical muscle training, using a proven exercise intervention strategy for chronic neck pain and headache, has been chosen as the model to investigate these questions. This exercise strategy has been chosen not only because it has been shown to be effective, but also because it does not conform to contemporary rationales for strength or endurance training. Thus while effective in relieving pain, it is unlikely to produce changes in these parameters. Thus other mechanisms are likely to be responsible for the clinical change. This research stands to make a significant contribution to exercise therapeutics by identifying the effective components of different exercise methods and investigating the pain relieving effects of the specific exercise. This knowledge will lead to the construction of a research based exercise program for neck pain patients, rather than have the current situation of often arbitrary choice of exercise.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.
Endocannabinoid-TRP Interactions In Midbrain Analgesic Pathways
Funder
National Health and Medical Research Council
Funding Amount
$586,903.00
Summary
Current pharmacotherapies for chronic pain are often ineffective. The active ingredient of the plant Cannabis sativa, THC, and a number of synthetic cannabinoids have efficacy in these pain states, however, they also produce a spectrum of adverse side-effects. This project will use cellular and behavioural techniques to examine how this cannabinoid system modulates intrinsic pain systems within the midbrain in order provide leads for novel analgesic pharmacotherapies with enhanced efficacy.
Irritable Bowel Syndrome (IBS) is one of the leading causes of chronic pain both world-wide and in Australia for which there is a lack of treatments. Chronic pain arises from nerve fibres in the colon wall, which fail to 'reset' back to normal following inflammation. Targeting these nerve endings with drugs is a key advance in IBS treatment. This project will identify selective oxytocin analogues that act in the colon to lower pain in sensory nerves thus providing efficacious pain relief in IBS.
Excitatory Interneurons: A Sensory Amplifier For Pathological Pain
Funder
National Health and Medical Research Council
Funding Amount
$649,848.00
Summary
Changes to the nervous system during pathological pain remain poorly understood. This poses a barrier to new and more effective pain therapies. We have recently shown that a population of excitatory nerve cells, which express a protein called calretinin, form an amplifier network within the spinal cord that enhances pain signalling. This application will determine how calretinin-positive nerve cells contribute to pathological pain and can subsequently be targeted to provide pain relief.
Targeting The Brain To Treat Chronic Pain Of Whiplash Associated Disorder
Funder
National Health and Medical Research Council
Funding Amount
$322,952.00
Summary
Chronic neck pain is the equal leading cause of disability worldwide. Guided by largely disproven structural pathology paradigms, treatment resources are directed to ‘fix’ musculoskeletal abnormalities, with at best small effects. Brain-imaging studies suggest that brain (rather than neck tissue) changes, may instead maintain pain. My research will test new brain-based treatments: The Tactile Training Device, and MoOVi Illusory Exercise Program and their effects on pain, disability and brain.