Cellular and Neurochemical Basis of Drug Addiction. Addiction to the major drugs of abuse, including heroin, amphetamines, cocaine, nicotine and alcohol damage the lives and cause premature death of more than 20% of Australians. Addiction produces long-term disruption of brain processes that lead to loss of control over urges to consume drugs and persistent cycles of relapse to drug taking. This research will apply new neurochemical approaches to discover mechanisms of disrupted brain function t ....Cellular and Neurochemical Basis of Drug Addiction. Addiction to the major drugs of abuse, including heroin, amphetamines, cocaine, nicotine and alcohol damage the lives and cause premature death of more than 20% of Australians. Addiction produces long-term disruption of brain processes that lead to loss of control over urges to consume drugs and persistent cycles of relapse to drug taking. This research will apply new neurochemical approaches to discover mechanisms of disrupted brain function that occur during development of addiction and relapse that are critical for development of better strategies to treat the disorder. Read moreRead less
Characterisation of monoaminergic transmission in Central Amygdala. This project will identify the distribution and function of dopamine, serotonin and noradrenalin receptors on the various cell types and their inputs, in the medial, lateral and capsular divisions of Central Amygdala (CeA). We will test for tonic endogenous activation of monoaminergic receptors and synaptic release from electrically stimulated fibers terminating in CeA. Using paired recordings and calcium imaging, we will invest ....Characterisation of monoaminergic transmission in Central Amygdala. This project will identify the distribution and function of dopamine, serotonin and noradrenalin receptors on the various cell types and their inputs, in the medial, lateral and capsular divisions of Central Amygdala (CeA). We will test for tonic endogenous activation of monoaminergic receptors and synaptic release from electrically stimulated fibers terminating in CeA. Using paired recordings and calcium imaging, we will investigate intracellular mechanisms underlying monoamine receptor mediated effects. These findings when correlated with published behavioural studies will provide greater understanding of the role of the divisions of CeA and the inputs they receive, in the function of the amygdala.Read moreRead less
Understanding the contribution of neuroinflammation in acute and chronic neural injury. A major focus of this project will be investigating the involvement of neuroinflammation in neural cell damage. It will explore how neuroinflammation contributes to this damage in both acute and chronic neuropathologies.
Investigating the mechanisms of flavonoid actions on glycine receptors. The research to be conducted in this project will use state-of-the-art electrophysiological and molecular biological approaches to carefully characterise the actions of certain flavonoid compounds on the glycine-receptor channel. These compounds have recently been reported to act as modulators of ligand-gated ion channels, proteins integral to brain function and disease. However, no-one has studied in any detail the mechan ....Investigating the mechanisms of flavonoid actions on glycine receptors. The research to be conducted in this project will use state-of-the-art electrophysiological and molecular biological approaches to carefully characterise the actions of certain flavonoid compounds on the glycine-receptor channel. These compounds have recently been reported to act as modulators of ligand-gated ion channels, proteins integral to brain function and disease. However, no-one has studied in any detail the mechanisms by which these compounds act. By discovering their site and mechanisms of action we will further our understanding of these important proteins and their modulation, maintain Australia's significant expertise in this field and provide leads for future development of drugs with potential therapeutic value.Read moreRead less
Activation mechanisms of Cys-loop ion channel receptors. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that proteins work. The information and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Cys-loop ligand-gated receptors have an essential role in brain function and are targets for many therapies and drug ....Activation mechanisms of Cys-loop ion channel receptors. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that proteins work. The information and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Cys-loop ligand-gated receptors have an essential role in brain function and are targets for many therapies and drugs of abuse. New insights into how biological ligands and drugs affect ion channel structure and function may lead to novel therapeutic opportunities and improved drug structure predictions.Read moreRead less
Toll Like Receptor signalling as a mediator of sex differences in pain, opioid and alcohol action. Brain immunology will be examined in this project to see if the signalling of a receptor called Toll Like Receptor 4 can explain sex differences in pain, and the action of pain killers and alcohol. These findings will have significant implications on the understanding of male and female brains, and will assist in the design of new drugs to treat brain and spinal cord diseases.
Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers ....Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers G protein-coupling to the intracellular portion of the GABA-BR2 subunit. Focus will be on different modes of GPCR signalling, including constitutive activity and roles for membrane and cytosolic regulatory proteins. Targeted studies of GABAB receptor subunits will provide new information on the mechanistic regulation of GPCR signalling.Read moreRead less
Using toxins to understand the mechanisms of pain. Toxins have evolved in plants, animals and microbes as part of defensive and/or prey capture strategies, and have proven to be invaluable research tools as well as providing leads for potential new therapies. This project will use subtype-selective toxins to define the role of ion channels in pain, using novel pathway-specific and disease-specific animal models of pain. The findings from this project will provide significant insight into the ne ....Using toxins to understand the mechanisms of pain. Toxins have evolved in plants, animals and microbes as part of defensive and/or prey capture strategies, and have proven to be invaluable research tools as well as providing leads for potential new therapies. This project will use subtype-selective toxins to define the role of ion channels in pain, using novel pathway-specific and disease-specific animal models of pain. The findings from this project will provide significant insight into the neuropharmacology of pain, will lead to the identification of novel molecular targets with analgesic potential and is expected to provide novel treatment approaches for pain.Read moreRead less
Pontine control of adaptive breathing behaviour in health and disease. This project will develop an understanding of the fundamental brain mechanisms associated with adaptive breathing during behaviour such as speech or swallowing. Adaptive breathing is impaired in lung disease, dementia and autism. This project will provide new insight to global brain function and treatment of central respiratory disorder.
A Pharmacological Approach To Define The Contribution Of Nav1.7 To Pain Pathways
Funder
National Health and Medical Research Council
Funding Amount
$501,467.00
Summary
Chronic pain is a debilitating condition that affects the life of one in five Australians and has significant socioeconomic impact. Currently available pain killers often do not work, or have intolerable side effects. We have discovered the most selective blocker for a specific type of sodium channel that is a known pain target and will use this novel molecule to gain insight into the mechanisms of pain and to develop new pain killers.