Synergism Between Opioids And Other Agents At Central Primary Afferent Synapses
Funder
National Health and Medical Research Council
Funding Amount
$202,771.00
Summary
Opioids, such as codeine, pethidine and morphine, are the most effective pain relieving drugs known but their clinical utility is limited by hazardous and potentially lethal side effects, as well as the development of tolerance and physical dependence with associated addiction liability. Recent research in our laboratory has identified for the first time a mechanism in the mammalian brain by which the pain relieving actions of opioids can be greatly enhanced by drugs that independently modulate ....Opioids, such as codeine, pethidine and morphine, are the most effective pain relieving drugs known but their clinical utility is limited by hazardous and potentially lethal side effects, as well as the development of tolerance and physical dependence with associated addiction liability. Recent research in our laboratory has identified for the first time a mechanism in the mammalian brain by which the pain relieving actions of opioids can be greatly enhanced by drugs that independently modulate biochemical processes distinct from those altered by opioids. Exploitation of these mechanisms has great potential for the development of new pharmacotherapies for effective pain relief with minimised side effects. These synergistic mechanisms appear to be at least as important for pain relief in the spinal cord as in brain, so the proposed studies will first examine the basis for synergism with opioid mediated pain relief in spinal cord. There is also strong evidence that the mechanisms to be studied in the proposed work are pivotal in the development of debilitating, chronic pain conditions that involve heightened sensitivity to painful stimuli and-or painful responses to normally innocuous stimuli such as light touch. Such aberrant responses can persist long after initial tissue damage has recovered. It is known that opioids can limit somewhat the initial steps in the induction of these abnormal responses but the mechanisms involved are unknown. The proposed studies will contribute to resolution of these mechanisms. Better understanding of the basis of these pathological processes will lead to better strategies for retarding or preventing the development of chronic pain conditions.Read moreRead less
Molecular Mechanism And Novel Activators Of Amino Acid And Calcium-sensing Class 3 G-protein Coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
When we eat protein-containing foods, our bodies extract twenty different amino acids for growth and tissue regeneration. Broad-spectrum amino acid sensing receptors detect the increases in blood amino acid levels and respond by triggering the release of biochemical signals. This project will establish the molecular rules by which these receptors work and identify novel activators with potential therapeutic application for the control of growth, tissue regeneration and calcium metabolism.
Cytochrome P450-mediated Epoxides Of Polyunsaturated Fatty Acids That Regulate Cell Death And Survival
Funder
National Health and Medical Research Council
Funding Amount
$495,710.00
Summary
Omega-3 polyunsaturated fatty acids (PUFAs) decrease cancer risk in man whereas omega-6 PUFA, which are common in western diets, increase risk. In cells cytochrome P450 converts PUFAs to epoxides. Omega-6 epoxides stimulate growth of cells and tumours but we have found that epoxides of the omega-3 eicosapentaenoic acid inhibit cell growth. We will now evaluate the mechanisms of these effects, which could lead to new anticancer treatments, perhaps based on altered diet.
Arachidonic Acid Modulation Of Glutamate Transporters
Funder
National Health and Medical Research Council
Funding Amount
$286,980.00
Summary
Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also fo ....Neurotransmitter transporters play a key role in regulating the dynamics of neurotransmission and are also the targets for a number of very important drugs. Glutamate is the predominant neurotransmitter responsible for fast excitatory neurotransmission and glutamate transporters are responsible for controlling glutamate concentrations to maintain normal neurotransmission. The failure of glutamate transporters has been implicated as playing a key role in brain damage following a stoke and also for long term neurological disorders such as Alzheimer's disease. In this project we shall investigate a novel mechanism for regulating the activity of glutamate transporters and explore the possibility of pharmacologically manipulating glutamate transporters. This work may lead to the development of novel compounds that improve transporter function and reduce the pathological consequences of impaired transporter function. Such compounds may have therapeutic potential as neuroprotectants in the treatment of neurological disorders such ischaemic brain damage or neurodegenerative disorders such Alzheimer's disease.Read moreRead less
HYPOXIA AND THE TRANSCRIPTIONAL REGULATION OF CYP GENES IN CELLS
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and ....Hypoxia, or oxygen deprivation caused by the decreased supply of blood to cells, is a component of ischaemic injury of the cardiovascular system (as in angina or atherosclerosis) and numerous other organs (e.g. in cancer and chemical-mediated injury). It is now known that the content of certain proteins that activate specialised target genes is increased rapidly in cells in response to oxygen deprivation. Some of the most important of these proteins are hypoxia-inducible factor-1 (or HIF-1) and activator protein-1 (or AP-1). We have identified a novel target gene that is activated in hypoxia. This gene produces an enzyme, termed cytochrome P450 2J2, that acts on fatty acids which are present in cell membranes and converts them into molecules that control the flow of potassium and calcium ions into cells. Alterations in the flow of such ions into cells have been observed previously in hypoxia but the mechanism of this effect is unclear. Thus, cytochrome P450 2J2 is switched on in hypoxia and generates fatty acid metabolites that control protective ion fluxes in cells.Read moreRead less
Alternate Signalling Pathways Regulating The Human Arachidonate Epoxygenase CYP2J2 In Response To Stress Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$369,000.00
Summary
Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid ....Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid products inside cells, is decreased in hypoxia and that this is due to increased activity of AP-1. We know that similar stressful stimuli can also result in a loss of CYP2J2. Again, AP-1 is involved but we have further evidence for the role of another pathway. This project will explore how these pathways operate individually and together to decrease CYP2J2. Studying the regulation of human genes is difficult because we can not readily monitor their levels in cells in either healthy or sick individuals. So we will make transgenic mouse models to study human CYP2J2 regulation, which will provide information on the human situation. In this project we will identify which factors switch off the CYP2J2 transgene and will analyse the signalling pathways within cells that control this response. The importance of these studies is that they will help us to design pharmacological strategies to prevent the loss of CYP2J2 in cells that are stressed. Such agents may be effective in the treatment of ischaemic injury seen in stroke and atherosclerosis. If we can maintain CYP2J2 levels we may be able to maintain the beneficial fatty acid levels in cells and have a novel therapeutic approach for keeping cells alive.Read moreRead less