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
Electroacupuncture On Opioid Consumption By Patients With Chronic Musculoskeletal Pain: A Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$368,138.00
Summary
Chronic musculoskeletal pain significantly impacts on productivity and quality of life and represents one-tenth of health expenditure. Opioids are increasingly prescribed to control this type of pain, although the long-term usage is inadequate and associated with significant adverse events. Our pilot study has shown that electroacupuncture (EA) is potentially beneficial for reducing OM. This study is to determine whether or not EA reduces OM consumption and associated adverse events.
Mechanisms Of Opioid Receptor Desensitisation In Single Neurons
Funder
National Health and Medical Research Council
Funding Amount
$301,320.00
Summary
Opioid drugs including morphine and codeine are the most effective analgesics known but their utility is limited by problems of tolerance (which is the need for increasing doses of drug to achieve the same effect), physical dependence characterised by a debilitating withdrawal syndrome on cessation of use, and addiction or compulsive drug seeking and use. Better understanding of the mechanisms underlying these adverse processes could lead to the development of more acceptable pain relieving agen ....Opioid drugs including morphine and codeine are the most effective analgesics known but their utility is limited by problems of tolerance (which is the need for increasing doses of drug to achieve the same effect), physical dependence characterised by a debilitating withdrawal syndrome on cessation of use, and addiction or compulsive drug seeking and use. Better understanding of the mechanisms underlying these adverse processes could lead to the development of more acceptable pain relieving agents. This project will increase understanding of the initial molecular events occurring in nerve cells that are believed to underlie the development of tolerance and physical dependence on opioid drugs. These studies will focus on sensory nerve cells isolated and cultured from animals, which are one of the major targets of pain relieving drugs. Understanding of these processes will lead to development of better strategies to avoid development of tolerance and perhaps physical dependence. They will also identify on a molecular level the mechanisms that determine why one opioid drug may produce more tolerance than another. This knowledge may lead to the development of pain relieving drugs that do not so readily lose their effectiveness in the management of chronic pain.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
Differentiation Of Multiple Phenotypes Of Rostral Ventromedial Medulla Neurons And Their Role In Pain
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Chronic pain, defined as pain experienced in three out of a six month pre-interview period affects 17% of males and 20% of females in the Australian population. Opioid drugs such as morphine and codeine are the most effective drugs used to treat moderate to severe pain. However, the utility of these drugs is hampered by the development of a blunted response with repeated use. Furthermore, some clinically important pain states, particularly those caused by nerve injury, do not respond well to opi ....Chronic pain, defined as pain experienced in three out of a six month pre-interview period affects 17% of males and 20% of females in the Australian population. Opioid drugs such as morphine and codeine are the most effective drugs used to treat moderate to severe pain. However, the utility of these drugs is hampered by the development of a blunted response with repeated use. Furthermore, some clinically important pain states, particularly those caused by nerve injury, do not respond well to opioid drugs. Recent basic neurosceince research has identified groups of nerve cells deep within the brain that control sensitivity to pain as pain signals enter the spinal cord. Unfortunately in the presence of some chronic pain conditions, or chronic use of high doses of opioid drugs, these neurons undergo functional changes or adaptations that distort and increase the severity of pain sensation in a more or less permanent manner. This project uses electrical and chemical techniques to identify the basic physiology and pharmacology of single nerve cells in this brain region, so that their normal functions can be properly understood. We will then identify the cellular and molecular adaptations that occur in the nerve cells in animal models of chronic nerve injury and chronic morphine treatment to identify the nature of adaptations responsible for their aberrant function. We will then be in a position to rationally identify novel drug targets that can normalise the function of these nerve cells. This knowledge will provide potential targets for development of novel therapeutics to manage chronic pain.Read moreRead less
Peripheral Mechanims Of Analgesia In Inflammatory Pain
Funder
National Health and Medical Research Council
Funding Amount
$181,018.00
Summary
This proposal will explore for the first time the interaction between the peripheral nervous system and the immune system and the effect on pain. Our preliminary studies highlight the direct interaction between the immune system and the nervous system as having an integral role in the control of pain in inflammation. Indeed these studies emphasis the impact of a compromised immune system on this inflammatory pain.
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
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 Mechanisms Responsible For Tolerance At The Mu-opioid Receptor
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Strong pain relieving opioid drugs like morphine lose their effectiveness when used for long periods because the single protein target for them in the body loses its� normal signalling functions. This research will determine the mechanisms responsible for this loss of function in brain nerve cells using novel methods to identify the molecular adaptations involved. This will provide a rational framework for development of pain relieving opioid drugs that can maintain long term efficacy.
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