The Role Of Presynaptic Inhibition In Neuropathic Pain
Funder
National Health and Medical Research Council
Funding Amount
$466,045.00
Summary
Inhibitory nerve cells in the spinal cord are thought to play an important role in governing the interaction between painful and non-painful stimuli. Defects in this process underlie allodynia, an important symptom of neuropathic pain. We will use recent advances in genetic techniques (optogenetics) to manipulate and study how inhibitory nerve cells separate touch and pain signalling in the spinal cord of normal and neuropathic animals.
Pain is one of the most frequent and costly health problems faced by Australia. Currently available painkillers often do not work, or have intolerable side effects. We thus need better approaches to treat pain. This project will define the role of the novel pain target Nav1.6 in clinically relevant pain states, including burns pain and chemotherapy-induced pain, with the aim to develop novel treatment approaches and painkillers for these difficult-to-treat conditions.
The Role Of Sodium Channels In Pain And Cold Allodynia
Funder
National Health and Medical Research Council
Funding Amount
$349,306.00
Summary
Many types of chronic pain remain poorly treated and severely impact the quality of life of millions of Australians. Cold allodynia in particular, which occurs in several painful human conditions and leads to severe pain from simply touching a cool surface or item, is poorly understood and thus difficult to treat. The aim of this project is to determine the pharmacological mechanism of cold allodynia to develop novel treatment approaches.
Professor Lewis is a molecular pharmacologist interested in discovering new venom peptides and ciguatoxins and determining how they interact with the membrane proteins they target using advanced biochemical and spectroscopic methods. Peptides of interest are then modified to improve potency and selectivity. Those with appropriate properties are patented and developed for clinical applications using approaches successfully applied to Xen2174, a conopeptide analogue I co-discovered that is now in ....Professor Lewis is a molecular pharmacologist interested in discovering new venom peptides and ciguatoxins and determining how they interact with the membrane proteins they target using advanced biochemical and spectroscopic methods. Peptides of interest are then modified to improve potency and selectivity. Those with appropriate properties are patented and developed for clinical applications using approaches successfully applied to Xen2174, a conopeptide analogue I co-discovered that is now in Phase II clinical trials for severe pain.Read moreRead less
The Role Of Proinflammatory Interleukin-17 (IL-17) And IL-17-producing T Cells In Neuropathic Pain
Funder
National Health and Medical Research Council
Funding Amount
$470,051.00
Summary
Peripheral nerve injury often results in persistent and debilitating neuropathic pain. My overall objective is to understand the immunological mechanisms responsible for such pain. I plan to test the hypothesis that the proinflammatory cytokine interleukin-17 promotes neuroinflammation and contributes to increased pain sensitivity after nerve injury. This study promises to enhance our understanding of neuroimmune activation in neuropathic pain and offers new opportunities for pain management.
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
Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones receive and process pain-signalling information from the skin ....Current treatments for chronic pain are limited in their success. This emphasises the need for new insights into the basic mechanisms and nervous system circuitry underlying altered or chronic pain states. Work in animals and patients with chronic pain shows that certain brainstem centres communicate, via descending spinal cord pathways, with small nerve cells in the superficial dorsal horn (SDH) of the spinal cord. These SDH neurones receive and process pain-signalling information from the skin and internal organs, and receive inputs from descending pathways. This descending input can either inhibit or enhance the activity of SDH neurones and subsequent pain perception. Till now it has been difficult to directly examine how descending pain pathways influence the small SDH neurones in the spinal cord. A new approach, which has been developed in our laboratory, now allows us to record from these very small SDH neurones in the spinal cord of an intact deeply anaesthetized mouse. In addition, our technique allows us to examine the recorded SDH neurone s responses to functionally relevant stimuli (brushing or pinching the hindpaw) as well as its physiology and anatomy. This project will use our new techniques to examine the effects of activating descending brainstem pathways that alter the way painful stimuli are processed in the spinal cord. The effects of altered levels of inhibition in the spinal cord will also be studied by using mice with naturally occurring mutations in their inhibitory glycine receptors. We believe a more complete understanding of pain processing mechanisms will be achieved by examining the role of descending pathways in an intact animal preparation. Such data are essential for the development of drug therapies that can successfully target pain syndromes.Read moreRead less