Targeting Neuron Memories to Treat Neuropathy

Today's post from Sciencedaily.com (see link below) looks at how traces of pain can be remembered by the brain. We're all familiar with the pain someone feels in a limb that has been removed or lost and this is basically because the brain remembers a 'reality', as if the limb were still there. Scientists are looking at how the manipulation of the protein kinase PKMzeta could possibly lead to a 'switching off' of the pain memory associated with nerve damage. If the protein can be targeted to block certain pain pathways, who knows what treatment possibilities may emerge.

Neuron Memory Key to Taming Chronic Pain, New Research Suggests
ScienceDaily (Feb. 13, 2012)

For some, the pain is so great that they can't even bear to have clothes touch their skin. For others, it means that every step is a deliberate and agonizing choice. Whether the pain is caused by arthritic joints, an injury to a nerve or a disease like fibromyalgia, research now suggests there are new solutions for those who suffer from chronic pain.

A team of researchers led by McGill neuroscientist Terence Coderre, who is also affiliated with the Research Institute of the McGill University Health Centre, has found the key to understanding how memories of pain are stored in the brain. More importantly, the researchers are also able to suggest how these memories can be erased, making it possible to ease chronic pain.

It has long been known that the central nervous system "remembers" painful experiences, that they leave a memory trace of pain. And when there is new sensory input, the pain memory trace in the brain magnifies the feeling so that even a gentle touch can be excruciating.

"Perhaps the best example of a pain memory trace is found with phantom limb pain," suggests Coderre. "Patients may have a limb amputated because of gangrene, and because the limb was painful before it was amputated, even though the limb is gone, the patients continue to feel they are suffering from pain in the absent limb. That's because the brain remembers the pain. In fact, there's evidence that any pain that lasts more than a few minutes will leave a trace in the nervous system." It's this memory of pain, which exists at the neuronal level, that is critical to the development of chronic pain. But until now, it was not known how these pain memories were stored at the level of the neurons.

Recent work has shown that the protein kinase PKMzeta plays a crucial role in building and maintaining memory by strengthening the connections between neurons. Now Coderre and his colleagues have discovered that PKMzeta is also the key to understanding how the memory of pain is stored in the neurons. They were able to show that after painful stimulation, the level of PKMzeta increases persistently in the central nervous system (CNS).

Even more importantly, the researchers found that by blocking the activity of PKMzeta at the neuronal level, they could reverse the hypersensitivity to pain that neurons developed after irritating the skin by applying capsaicin -- the active ingredient in hot peppers. Moreover, erasing this pain memory trace was found to reduce both persistent pain and heightened sensitivity to touch.

Coderre and his colleagues believe that building on this study to devise ways to target PKMzeta in pain pathways could have a significant effect for patients with chronic pain. "Many pain medications target pain at the peripheral level, by reducing inflammation, or by activating analgesia systems in the brain to reduce the feeling of pain," says Coderre. "This is the first time that we can foresee medications that will target an established pain memory trace as a way of reducing pain hypersensitivity. We believe it's an avenue that may offer new hope to those suffering from chronic pain."

Other contributing researchers on this study include Andre Laferrière, Mark H Pitcher, Anne Haldane, Yue Huang, Virginia Cornea, Naresh Kumar, Fernando Cervero (all from the Alan Edwards Centre for Research on Pain at McGill) and co-author Todd C Sacktor (State University of New York Downstate Medical Center).

This research was supported by grants from Canadian Institutes of Health Research (CIHR), the Louise and Alan Edwards Foundation, National Institutes of Health (NIH) and an Astra-Zeneca/AECRP fellowship.

http://www.sciencedaily.com/releases/2012/02/120213154141.htm

Targeting Neuropathy Treatment Better

Today's post from sciencedaily.com (see link below) looks at the studies being made at atomic and molecular level to find ways of treating neuropathic pain more directly and accurately. One of the more extreme and excruciatingly painful, neurological conditions is erythromelagia  ('Man on Fire syndrome'). Scientists have found a mutation at molecular level in the sodium channels of patients and seen that because it responds well to carbamazepine for instance, identifying that mutation may lead to better targeted drug treatment in the future. Talking about sodium channels, genetic analysis and specific amino acids will leave most people cold but the important thing is that scientists are now looking much more closely at specific pain reactions to specific drugs. This can only lead to better treatment for neuropathy sufferers in the future as we know that it's not a 'one size fits all' disease. At the moment, drugs meant for other problems are thrown at neuropathy in the hope that one eventually works. Hopefully in the future. much of the guesswork will be removed.

'Man On Fire Syndrome': In a World of Chronic Pain, Individual Treatment Possible, Research Shows
ScienceDaily (Nov. 13, 2012)
 
An investigation into the molecular causes of a debilitating condition known as "Man on Fire Syndrome" has led Yale researchers to develop a strategy that may lead to personalized pain therapy and predict which chronic pain patients will respond to treatment.

More than a quarter of Americans suffer from chronic pain and nearly 40 percent do not get effective relief from existing drugs. In many common conditions such as diabetic neuropathy, no clear source of pain is found.

The new study published in the Nov. 13 issue of Nature Communications used sophisticated atomic modeling techniques to search for mutations found in a rare, agonizing, and previously untreatable form of chronic pain called erythromelagia, commonly referred to as "Man on Fire Syndrome." Researchers discovered that one of those mutations seem to predicted whether a patient would respond positively to drug treatment.

"Hopefully we can use this knowledge to help chronic pain patients in more systematic ways, and not depend upon trial and error," said Yang Yang, postdoctoral research associate in the Department of Neurology and lead author of the paper.

Under the leadership of Stephen Waxman, the Bridget Marie Flaherty Professor of Neurology, professor of neurobiology and of pharmacology, and senior author of the new paper, Yale has been a leader in identifying the sodium channel Nav1.7 at the base nerve cells as the regulator of several forms of chronic pain. The members of the Waxman lab were intrigued when it was reported the anti-seizure medicine carbamazepine relieved pain in members of a family suffering from erythromelagia, apparently by working on the Nav 1.7 sodium channel.

Yale researchers conducted an exhaustive genetic analysis and discovered that a specific variant -- a difference of a single amino acid among 1,800 -- in the sodium channel explained why this family responded to the drug. In this new paper, the Yale team developed a three-dimensional structural model of human Nav1.7 channel and systemically looked at different erythromelagia mutations at the atomic level. The Yale team found an additional, second mutation that was sensitive to carbamazepine treatment. In theory, chronic pain patients with this mutation should respond to treatment with carbamazepine.

"This work shows us that the goal of personalized, genomically-guided drug treatment for pain is not unrealistic," Waxman said.

The U.S. Department of Veterans Affairs funded the work.

Other Yale authors include Sulayman D. Dib-Hajj, Lynda Tyrrell, and Mark Estacion.

http://www.sciencedaily.com/releases/2012/11/121113122040.htm