Opioid Actions On Sensory Neuron Excitability In Vitro
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
Morphine and related drugs are very widely used for pain relief, although the way they affect the pain-sensitive cells in the body is not well understood. Use of morphine for extended periods of time often makes morphine less effective for pain relief, which makes it necessary to increase the dose of morphine given. This leads to an increase in the unwanted side effects of morphine, and can eventually lead to morphine becoming ineffective in controlling pain. This study is designed to examine ho ....Morphine and related drugs are very widely used for pain relief, although the way they affect the pain-sensitive cells in the body is not well understood. Use of morphine for extended periods of time often makes morphine less effective for pain relief, which makes it necessary to increase the dose of morphine given. This leads to an increase in the unwanted side effects of morphine, and can eventually lead to morphine becoming ineffective in controlling pain. This study is designed to examine how morphine affects pain-sensitive cells, and to determine how continued use of morphine changes the way pain-sensitive cells respond to morphine. We hope that by understanding how morphine works on pain-sensitive cells, we can understand why it does not work so well after continued use. This information should enable us to design better forms of pain relief than we have now.Read moreRead less
Molecular Pharmacology And Physiology Of Glycine Transport
Funder
National Health and Medical Research Council
Funding Amount
$170,274.00
Summary
The simple amino acid glycine plays an important role in many metabolic events in the body and in the mammalian central nervous system glycine has additional functions as a neurotransmitter. In the spinal cord and brain stem, glycine acts as an inhibitory neurotransmitter through activation of glycine receptors. In the brain, glycine may also act as an excitatory neurotransmitter through its action as a co-activator with glutamate at the NMDA subtype of glutamate receptors. This project will add ....The simple amino acid glycine plays an important role in many metabolic events in the body and in the mammalian central nervous system glycine has additional functions as a neurotransmitter. In the spinal cord and brain stem, glycine acts as an inhibitory neurotransmitter through activation of glycine receptors. In the brain, glycine may also act as an excitatory neurotransmitter through its action as a co-activator with glutamate at the NMDA subtype of glutamate receptors. This project will address the issue as to whether glycine transporters have the capacity to regulate glycine concentrations within excitatory synapses and thereby play an active role in regulating neurotransmission. This work will form the basis for understanding the role that glycine plays in normal brain functions, such as learning and memory, and also under pathological conditions following a stroke. This work will also serve as a basis for assessing the therapeutic potential of manipulating glycine concentrations in the treatment of neurological disorders, such as schizophrenia.Read moreRead less
Opioid Actions On Identified Sensory Neurons In Vitro
Funder
National Health and Medical Research Council
Funding Amount
$371,850.00
Summary
Opioids (in particular morphine) are the gold standard drugs for the relief of most types of moderate to severe pain. Despite the effectiveness of opioids and other analgesics, many people still suffer unrelieved pain. There are 2 main reasons for this. Firstly, there are some types of pain that are refractory to currently used analgesics from the outset, and secondly, chronic conditions may require escalating doses of analgesics for adequate pain relief, and these does may increase until side e ....Opioids (in particular morphine) are the gold standard drugs for the relief of most types of moderate to severe pain. Despite the effectiveness of opioids and other analgesics, many people still suffer unrelieved pain. There are 2 main reasons for this. Firstly, there are some types of pain that are refractory to currently used analgesics from the outset, and secondly, chronic conditions may require escalating doses of analgesics for adequate pain relief, and these does may increase until side effects become intolerable. My studies will provide insight into the reasons that underlie the differential effectiveness of opioids in acute pain conditions, as well as the reasons why opioids lose their effectiveness over time. These studies will also identify molecular targets that may be important for developing analgesics for specific pain conditions. Because the head is the source of many familiar painful conditions, including tooth pain, migraine and temporomandibular disorders, I will be using neurons from the trigeminal ganglion, the part of the nervous system which supplies the sensory innervation to the structures involved in these pain states. By using mice as experimental animals, I will be able to investigate the contribution of neurons that innervate specific parts of the head to these pain states, and study how chronic morphine treatment affects the behavior of these cells. I hope that these studies will provide a basis for designing strategies that improve the effectiveness of existing analgesics, and perhaps lead to the identification of new, better pain relievers.Read moreRead less
Molecular Interactions Of Novel Conotoxin Inhibitors Of The Noradrenaline Transporter
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these pate ....A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these patented peptides to be used as leads to the development of a new class of therapeutic for controlling the adverse effects of inadequate noradrenaline balance.Read moreRead less
Glycine Transporters regulate the concentration of glycine in the spinal cord and brain. It has been suggested that elevating glycine levels in these regions may be useful in treating pain and schizophrenia. This project will provide the basis for the development of new glycine transport inhibitors that may be used to treat these conditions.
The In Vivo And In Vitro Biology Of The Novel Intracellular Ion Channel CLIC1 (NCC27)
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Ion channels are complex proteins that regulate the transports of salts, and essential cell function. We have recently cloned a new ion channel, CLIC1, unique in its location on the nuclear membrane as well as other sites. The function of this channel is uncertain, although we have suggested its association with cell growth and inflammation. We propose to investigate the function of CLIC1, dominantly based on gene knockout animals, in which the CLIC1 gene has been deleted.
Understanding Local And Regional Determinants Of EDHF And NO Dysfunction In Resistance Arteries In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$771,295.00
Summary
Diabetes is a serious and increasing health burden worldwide. Most of the sickness and death associated is due to complications arising in the blood vessels. The inner lining of blood vessels in small arteries uses several different mechanisms to ensure proper blood flow, and in diabetes these are impaired. This study will reveal the cellular mechanisms involved and identify pathways for therapeutic intervention to alleviate the debilitating effects of small artery disease.
The Pharmacology And Physiology Of GABA-C Receptors
Funder
National Health and Medical Research Council
Funding Amount
$481,980.00
Summary
GABA is one of the most important chemicals in the brain. GABA and its associated receptors (GABA receptors) work together to keep the balance between neuronal excitation and inhibition which is required for normal brain function. There are three types of GABA receptors called GABA-A, GABA-B and GABA-C receptors. Chemicals acting at these receptors may be therapeutically useful in treating neurological probles such as epilepsy, anxiety, depression and memory-related disorders associated with Alz ....GABA is one of the most important chemicals in the brain. GABA and its associated receptors (GABA receptors) work together to keep the balance between neuronal excitation and inhibition which is required for normal brain function. There are three types of GABA receptors called GABA-A, GABA-B and GABA-C receptors. Chemicals acting at these receptors may be therapeutically useful in treating neurological probles such as epilepsy, anxiety, depression and memory-related disorders associated with Alzheimer's disease and schizophrenia. GABA-A and GABA-C receptors are members of the ligand-gated ion channel super family in which the ion channel forms an intergral and central part of the receptor. In response to GABA, the channel opens and chloride ions flow through the channel. This causes an inhibitory action i.e. the cell reduces its rate of firing. This project aims to study GABA-C receptors by investigating what proteins make up the ion channel, by studying the actions of a range of chemicals that have specific effects at these receptors and by identifying amino acids that are important for normal channel function. New chemicals identified in our studies will provide leads for the design and development of new therapeutic agents acting on the brain.Read moreRead less