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.
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
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
Identification And Characterization Of Novel Bioactive Peptides From Australian Conesnails Targeting Pain Pathways
Funder
National Health and Medical Research Council
Funding Amount
$320,803.00
Summary
In recent years, significant advances have been made in the identification of new targets in the central or peripheral nervous systems which may be used to develop new pain killers. However, molecules specifically targeting these receptors and channels are lacking to date. This project will use novel cell-based approaches to find new molecules from conesnails which specifically target receptors involved in pain. These will be useful to increase our understanding of the mechanisms of pain.
Alteration Of Glucose Metabolism By GPCR Activation
Funder
National Health and Medical Research Council
Funding Amount
$444,796.00
Summary
In type 2 diabetes the effect of insulin to stimulate glucose transport in fat cells and skeletal muscle is impaired so there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G protein-coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose homeostasis and will evaluate them as potential treatments.
Urotensin-II In Human Heart: Investigation Of Mechanisms Involved In Cardiac Function
Funder
National Health and Medical Research Council
Funding Amount
$255,990.00
Summary
The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our finding ....The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our findings indicate that urotensin-II is the most potent heart stimulator identified to date. In patients with heart failure, short term stimulation of heart contraction is beneficial, supplying the heart and other organs with vital oxygen and nutrients. However, in the long term excessive stimulation causes worsening of the patients condition. Very little is currently known about the way in which urotensin-II alters heart function. The goal of our study is to understand the mechanism involved in urotensin-II mediated effects on the heart. This will involve identifying the location of urotensin-II and its receptors in the heart, and determining what signalling changes occur after the interaction of urotensin-II with its receptors. Urotensin-II must first be cleaved from a larger drug. We will determine where in the heart this cleavage occurs and whether the process is crucial to the ability of urotensin-II to stimulate contraction of the heart. Since stimulators of heart contraction are detrimental to patients with heart failure in the long term, we will determine whether these patients have more urotensin-II in their blood than patients who do not have heart failure. If the levels of urotensin-II are higher in heart failure patients, it may indicate a need to interfere with the interaction of urotensin-II with its receptors.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