Molecular Mechanisms Of G Protein-Coupled Receptor Cross Talk
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aber ....The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aberrations in the normal function of these G protein-coupled receptors have been implicated in a wide variety of disorders, such as schizophrenia, pain and dementia. To date, most therapeutic approaches to treating these disorders have targeted individual types of G protein-coupled receptors thought to play a role in each disease state, but this has met with mixed success. One of the reasons for this is that each disorder actually involves more than one type of G protein-coupled receptor communicating with other types in a complex way. Our current proposal specifically focuses on some of the newer mechanisms that have been suggested to play an important role in the communication between different types of G protein-coupled receptors located in the same type of cell. An understanding of how such receptor proteins can communicate with one another in this situation is absolutely vital in unravelling processes involved in the maintenance of health, abnormalities that lead to disease and in the development of more effective treatments.Read moreRead less
Opioids are the most important drugs used to treat moderate to severe pain, however the development of tolerance limits their usefulness. In addition, clinically important pain states, particularly neuropathic pain, are insensitive to opioid treatment. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabinoids also have analgesic, or pain relieving properties. Of particular interest is the finding that cannabinoids enhan ....Opioids are the most important drugs used to treat moderate to severe pain, however the development of tolerance limits their usefulness. In addition, clinically important pain states, particularly neuropathic pain, are insensitive to opioid treatment. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabinoids also have analgesic, or pain relieving properties. Of particular interest is the finding that cannabinoids enhance the analgesic actions of opioids. Several brain regions are known to play a pivotal role in the analgesic actions of both opioids and cannabinoids. In previous studies I have identified the cellular and molecular mechanisms by which opioid drugs produce their analgesic effects in single brain cells. However, the cellular mechanisms underlying cannabinoid induced analgesia within the brain are poorly understood. In addition, the cellular actions of cannabinoids and opioids in neuropathic pain states are unknown. The proposed study will determine the cellular and molecular mechanisms underlying the analgesic actions of cannabinoids and opioids in single brain neurons in normal and neuropathic pain states. These techniques have the potential to identify antinociceptive combinations between cannabinoids and other agents with enhanced efficacy and reduced side effects.Read moreRead less
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
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.
Cellular Actions Of Cannabinoids Within The Spinal Cord Dorsal Horn In A Neuropathic Pain State
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Morphine and other opioids are among the most important drugs used to treat moderate to severe pain. However, some clinically important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic pain which is caused by injury to the nervous system. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have analgesic, or pain relieving properties. Animal studies ....Morphine and other opioids are among the most important drugs used to treat moderate to severe pain. However, some clinically important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic pain which is caused by injury to the nervous system. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have analgesic, or pain relieving properties. Animal studies have shown that cannabinoids potentiate the analgesic effects of opioids. Of particular interest is the finding that cannabinoids reduce the abnormal pain symptoms associated with animal models of neuropathic pain, such as that caused by nerve injury. Several brain regions play a pivotal role in the analgesic actions of both opioids and cannabinoids. In previous studies I have identified the cellular mechanisms by which opioids and cannabinoids produce their analgesic effects in single cells within the brain. In addition, the spinal cord is the initial relay point of painful stimuli entering the central nervous system and is a major site of opioids and cannabinoid analgesic actions. However, the cellular mechanisms underlying cannabinoid and opioid actions within the spinal cord, particularly in pathways which transmit ascending pain information to the brain, are less well understood. In addition, the cellular actions of cannabinoids and opioids in neuropathic pain states are unknown. The proposed study will determine the cellular mechanisms underlying the analgesic actions of cannabinoids and opioids in single neurons identified as belonging to pain pathways within the spinal cord in normal and nerve injured animals. These techniques have the potential to identify analgesic combinations between cannabinoids, opioids and other agents with enhanced therapeutic activity and reduced side effects.Read moreRead less
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how each of these components, the stimulating agent, the receptor and G protein, works in order to understand how the cells respond to various chemical signals. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. Understanding what actually is the role of these new players, and how they team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less
How Do P75 And Sortilin Facilitate TrkA-mediated Survival Signalling?
Funder
National Health and Medical Research Council
Funding Amount
$559,354.00
Summary
Neurotrophins are the classical growth factors that regulate neuronal survival and death throughout the nervous system in both the developing and adult animal. These factors signal through one of three receptors, but precisely how the receptors interact to propagate cell survival is unclear. The goal of this grant is to unravel the molecular basis underpinning this life and death signalling decision so that we can then devise ways to promote cell survival in neurodegenerative conditions
Molecular Characterisation Of Receptor Activity Modifying Proteins (RAMPs)
Funder
National Health and Medical Research Council
Funding Amount
$340,399.00
Summary
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore, extremely important to unravel how each of these components works. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. We have shown that RAMPs interact with many G protein-coupled receptors and that they have a wider range of actions than has previously been appreciated. Moreover, it has been shown that the RAMP-receptor interface is a viable target for drug development. Understanding the extent to which RAMPs interact with G protein-coupled receptors, how they interact with the receptors and the consequences of this interaction forms the basis of the current proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less