Investigation Of Neural Mechanisms Of 670 And 830nm Laser Acupuncture In Pain Relief, Using Rat
Funder
National Health and Medical Research Council
Funding Amount
$326,207.00
Summary
Background Chronic pain is common and costs $10 billion dollars per year in Australia. Drug therapies are widely used but serious side effects limit use. Patients actively seek non-drug treatments and laser acupuncture is one of the most commonly sought therapies for chronic pain, however, how it works is not well understood. Our previous work Researchers propose that laser acupuncture reduces pain by direct effects on nerves, altering how pain signals are transmitted to the brain. To investigat ....Background Chronic pain is common and costs $10 billion dollars per year in Australia. Drug therapies are widely used but serious side effects limit use. Patients actively seek non-drug treatments and laser acupuncture is one of the most commonly sought therapies for chronic pain, however, how it works is not well understood. Our previous work Researchers propose that laser acupuncture reduces pain by direct effects on nerves, altering how pain signals are transmitted to the brain. To investigate this we (CI A and CI B) previously undertook a study of infrared laser on nerve cell cultures. This followed on from a positive clinical study with the same laser wavelength in the treatment of neck pain, undertaken by CI B. We established that laser temporarily interrupts the nerve transport system, which is made up of a series of minute tubes, called microtubules. These act as a “monorail” system for transport of mitochondria, which provide energy for all nerve functions. We propose that temporary interruption of this system, called fast axonal transport, disrupts the conduction of pain signals along the nerve, resulting in pain relief. Important unanswered questions The mechanism by which 830nm laser acupuncture relieves pain clinically remains poorly understood. For its acceptance into mainstream clinical practice it is important to determine the effect of laser on the peripheral nerves and in particular the pain carrying fibres. We know from an earlier study that a single exposure causes significant but reversible changes in pain fibres including axonal microtubule disruption, decrease in mitochondrial membrane potential and block of fast axonal flow. These events would result in conduction failure. The question is whether the repeated irradiations, comparable to those delivered clinically result in the same changes. This would provide a scientific basis for understanding the clinical effectiveness of laser acupuncture. We also do not know if 670nm laser acupuncture would act in the same way. There is evidence that this may be more effective so that this remains another important unanswered question. Further, there is no evidence regarding which wavelength would be cost and time effective as it is desirable to deliver lower dose. We need to determine the most effective dose and wavelength so that clinical trials could be carried out as was done for the trials by CIB (Chow and Barnsley, 2006).Read moreRead less
Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which w ....Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which we have shown to operate in various smooth muscles. This mechanism, termed store-based pacemaking, is entirely different to the currently held cardiac model but could readily achieve the same outcome. We will investigate the hypotheses that this pacemaker mechanism is also fundamental to mammalian heart pacemaking and conduction. Positive support for our hypotheses, as indicated by our findings on amphibian hearts and from pilot findings, may severely challenge the present model for cardiac pacemaking. Such an outcome will have major ramifications on present interpretation of cardiac function in health and disease and will be particularly important to interpretation of disorders associated with cardiac arrhythmias and heart conduction.Read moreRead less
The Role Of T-cell Apoptosis In Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$173,380.00
Summary
Organ transplantation is the treatment of choice for patients with end-stage heart, lung, liver or kidney failure and there have been spectacular improvements in the early success of these procedures. However the 10 year graft survival rate has not changed much in the past 15 years. One way of overcoming this problem is to manipulate the immune system so that the transplant is accepted indefinitely. This is called tolerance and it works by giving intense immunosuppression for a short period so t ....Organ transplantation is the treatment of choice for patients with end-stage heart, lung, liver or kidney failure and there have been spectacular improvements in the early success of these procedures. However the 10 year graft survival rate has not changed much in the past 15 years. One way of overcoming this problem is to manipulate the immune system so that the transplant is accepted indefinitely. This is called tolerance and it works by giving intense immunosuppression for a short period so that the transplant is accepted indefinitely without the need for long term immunosuppression. The immune mechanism responsible for this phenomenon is complex and is poorly understood. This project aims to study the early events in the immune system that leads to transplantation tolerance. In particular, factors involved in programmed cell death in white blood cells will be studied. Specially bred mice that have blocks in the cell death mechanisms will used to determine what effects these blocks have on the ability to induce tolerance. Other mice that have been genetically altered to allow their white cells to be tracked will be used to study the fate of these cells. If the mechanisms involved in tolerance induction are better understood, then it will be possible to design specific immunosuppressive drugs that will be used to produce tolerance in transplant patients.Read moreRead less
Renal Medullary Blood Flow: Regulation By Paracrine, Endocrine And Neural Factors
Funder
National Health and Medical Research Council
Funding Amount
$410,616.00
Summary
High blood pressure is a condition afflicting more than 10% of our community, and is the leading risk factor for stroke and heart disease. The kidneys play a critical role in control of blood pressure under normal conditions, and probably also in the initiation and maintenance of high blood pressure. This influence is exerted both through the excretion of salt and water, and by the release of substances into the circulation that affect blood pressure (hormones). Recent experiments performed by u ....High blood pressure is a condition afflicting more than 10% of our community, and is the leading risk factor for stroke and heart disease. The kidneys play a critical role in control of blood pressure under normal conditions, and probably also in the initiation and maintenance of high blood pressure. This influence is exerted both through the excretion of salt and water, and by the release of substances into the circulation that affect blood pressure (hormones). Recent experiments performed by us and others have indicated that the inner part of the kidney (the medulla) is critical in these functions, which appear to be regulated by the level of blood flow in the medulla of the kidney. Our recent experiments also show that hormones and nerves have diverse effects on blood flow in the different regions of the kidney, showing that these factors can differentially affect blood pressure depending on their effects on medullary blood flow. Importantly, these hormones and nerves do not act in isolation, but act in concert, and in association with so called 'second messenger' systems that act locally to directly affect the contraction of muscle in blood vessels, and so blood vessel size. The experiments described in this application are aimed at determining how circulating and locally acting hormones, and the nerves in the kidney, interact together to control blood flow in the different regions of the kidney. This will help us understand how blood flow to the medulla of the kidney is regulated normally, so that we can begin to understand how malfunction of these systems can contribute to the development of high blood pressure.Read moreRead less
Mitochondrial Dysfunction And Pathways Of Cell Death In Drug-induced Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$301,650.00
Summary
Drugs are an important cause of liver disease that can result in fatal liver damage or require liver transplantation. More than 500 drugs are reported to cause liver disease, but we know almost nothing about how drugs injure the liver. As well as prescribed drugs: panadol, either after self-poisoning or inadvertently taken in too high a dose in someone who is not eating or is taking other medications that interfere with panadol breakdown, is one of most common causes of acute liver failure. Furt ....Drugs are an important cause of liver disease that can result in fatal liver damage or require liver transplantation. More than 500 drugs are reported to cause liver disease, but we know almost nothing about how drugs injure the liver. As well as prescribed drugs: panadol, either after self-poisoning or inadvertently taken in too high a dose in someone who is not eating or is taking other medications that interfere with panadol breakdown, is one of most common causes of acute liver failure. Further, several herbal medicines have been implicated as causing liver disease. This project is designed to help us understand why and how 3 particular drugs damage the liver. We will study panadol, diterpenoids the active ingredients of skullcap, a herbal medicine, and azathioprine (imuran), a drug commonly used to suppress rejection after kidney or liver transplantation which occasionally causes very severe liver disease. Our main hypothesis is that these drugs damage mitochondria, the energy generating structures that form the engine of all living cells. We already know a little about how drug metabolites of panadol and the diterpenoids can damage mitochondria, but no-one has proven that this is the most important way in which they damage the liver. For drugs like azathioprine in which liver damage is rare, we are proposing that genetic defects in the mitochondrial DNA are what could predispose to liver injury. Thus our measurements will include how much mitochondrial DNA damage is caused by the drugs. Panadol, diterpenoids and azathioprine cause liver cell death by differing pathways (called apoptosis and necrosis). There are plausible ways in which mitochondrial damage could start off either (or both) cell death pathways during drug-induced liver injury, and we plan to test these. The new knowledge gained about how drugs damage the liver will be instrumental in allowing us to design new approaches to treat this important problem.Read moreRead less
The glomerulus is the filtering component of the kidney. In many diseases, it can be the target of an inappropriate inflammatory response. As part of this response, white blood cells accumulate in the glomerulus where they cause damage. The aim of the project is to determine how these white blood cells accumulate in the glomerulus, specifically asking the question, what molecules present on the white blood cells and the glomerular blood vessels are required for this accumulation?