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
Role Of GAT-1 Transporter Channels In Opioid Dependence
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
Opioid drugs including heroin and morphine are very addictive. After cessation of chronic use of these drugs an intensely unpleasant withdrawal syndrome develops that contributes to relapse. Brain mechanisms that produce withdrawal are still poorly understood. The present work will determine the pathological cellular and molecular mechanisms that produce withdrawal in inhibitory brain nerve cells known to be involved in generating withdrawal discomfort and relapse to compulsive drug use.
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
Novel Delta Receptor Expression In Opioid Tolerant/dependent Neurons
Funder
National Health and Medical Research Council
Funding Amount
$370,350.00
Summary
Opioids such as morphine and heroin act on specific molecular targets, or receptors, in the brain. Long term use of opioids produce changes in brain receptor systems that greatly diminish the effects of these drugs (tolerance), as well as producing an adverse withdrawal syndrome on cessation of use (physical dependence). The present proposal will identify the mechanisms of adaptations in cellular function in nerve cells critical for these changes. In particular, we have identified enhanced sensi ....Opioids such as morphine and heroin act on specific molecular targets, or receptors, in the brain. Long term use of opioids produce changes in brain receptor systems that greatly diminish the effects of these drugs (tolerance), as well as producing an adverse withdrawal syndrome on cessation of use (physical dependence). The present proposal will identify the mechanisms of adaptations in cellular function in nerve cells critical for these changes. In particular, we have identified enhanced sensitivity of receptor, the delta receptor, that is closely related to the opioid receptor but is not a target for heroin or morphine. We will identify the mechanisms of enhanced activity of this receptor after chronic use of morphine with a view to tergeting therapeutics to manage tolerance and physical dependence in opioid addicts and chronic pain patients.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
Pharmacogenetics Of Methadone Maintenance Treatment
Funder
National Health and Medical Research Council
Funding Amount
$355,564.00
Summary
There is large amount of inter-individual variability in response to methadone use in dependence programmes. Many factors are involved including age, disease and the use of other drugs. Until recently a person's genetic makeup was not amongst these factors. Our study will show how genetic variability that alters the transport or the drug target in the body impacts on a person's drug response and side effects to methadone used to treat opioid dependence.
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
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.
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