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
Molecular Targets Of Amino Acid/neurotransmitter Conjugates Of Fatty Acids
Funder
National Health and Medical Research Council
Funding Amount
$846,390.00
Summary
This project investigates endogenous chemicals that affect cells important for detecting and responding to pain. We aim to discover how these compounds affect proteins important for nerve cell function, particularly proteins that have a prominent role in detecting and transmitting painful events. The compounds we examine are not themselves likely to be drugs, but future therapies may involve manipulating the levels of these chemicals in the body, or using drugs that mimic the activity of these c ....This project investigates endogenous chemicals that affect cells important for detecting and responding to pain. We aim to discover how these compounds affect proteins important for nerve cell function, particularly proteins that have a prominent role in detecting and transmitting painful events. The compounds we examine are not themselves likely to be drugs, but future therapies may involve manipulating the levels of these chemicals in the body, or using drugs that mimic the activity of these compounds.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
I am a biochemist-pharmacologist determining how neurotransmitter transporters work, which will aid in the development in novel therapies for disorders of the nervous system
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