Posts tagged pain

ScienceDaily (Aug. 21, 2012) — Working with units of material so small that it would take 50,000 to make up one drop, scientists are developing the profiles of the contents of individual brain cells in a search for the root causes of chronic pain, memory loss and other maladies that affect millions of people.

They described the latest results of this one-by-one exploration of cells or “neurons” from among the millions present in an animal brain at the 244^th National Meeting & Exposition of the American Chemical Society (ACS), the world’s largest scientific society. The meeting, expected to attract almost 14,000 scientists and others from around the world, continues in Philadelphia through Thursday, with 8,600 presentations on new discoveries in science and other topics.

Jonathan Sweedler, Ph.D., a pioneer in the field, explained in a talk at the meeting that knowledge of the chemistry occurring in individual brain cells would provide the deepest possible insights into the causes of certain diseases and could point toward new ways of diagnosis and treatment. Until recently, however, scientists have not had the technology to perform such neuron-by-neuron research.

"Most of our current knowledge about the brain comes from studies in which scientists have been forced to analyze the contents of multiple nerve cells, and, in effect, average the results," Sweedler said. He is with the University of Illinois at Urbana-Champaign and also serves as editor-in-chief of Analytical Chemistry, which is among ACS’ more than 40 peer-reviewed scientific journals. “That approach masks the sometimes-dramatic differences that can exist even between nerve cells that are shoulder-to-shoulder together. Suppose that only a few cells in that population are changing, perhaps as a disease begins to take root or starts to progress or a memory forms and solidifies. Then we would miss those critical changes by averaging the data.”

However, scientists have found it difficult to analyze the minute amounts of material inside single brain cells. Those amounts are in the so-called “nanoliter” range, units so small that it would take 355 billion nanoliters to fill a 12-ounce soft-drink can. Sweedler’s group spent much of the past decade developing the technology to analyze the chemicals found in individual cells — a huge feat with a potentially big pay-off. “We are using our new approaches to understand what happens in learning and memory in the healthy brain, and we want to better understand how long-lasting, chronic pain develops,” he said.

The 85 billion neurons in the brain are highly interconnected, forming an intricate communications network that makes the complexity of the Internet pale in comparison. The neural net’s chemical signaling agents and electrical currents orchestrate a person’s personality, thoughts, consciousness and memories. These connections are different from person to person and change over the course of a lifetime, depending on one’s experiences. Even now, no one fully understands how these processes happen.

To get a handle on these complex workings, Sweedler’s team and others have zeroed in on small sections of the central nervous system ― the brain and spinal cord ― using stand-ins for humans such as sea slugs and laboratory rats. Sweedler’s new methods enable scientists to actually select areas of the nervous system, spread out the individual neurons onto a glass surface, and one-by-one analyze the proteins and other substances inside each cell.

One major goal is to see how the chemical make-up of nerve cells changes during pain and other disorders. Pain from disease or injuries, for instance, is a huge global challenge, responsible for 40 million medical appointments annually in the United States alone.

Sweedler reported that some of the results are surprising, including tests on cells in an area of the nervous system involved in the sensation of pain. Analysis of the minute amounts of material inside the cells showed that the vast majority of cells undergo no detectable change after a painful event. The chemical imprint of pain occurs in only a few cells. Finding out why could point scientists toward ways of blocking those changes and in doing so, could lead to better ways of treating pain.

Source: Science Daily

July 27, 2012 

(Medical Xpress) — Johns Hopkins scientists have discovered a “scaffolding” protein that holds together multiple elements in a complex system responsible for regulating pain, mental illnesses and other complex neurological problems.

Preso1 (green) and mGluR5 (red) appear in the same location inside a neuron.

The finding, published in the May 6 issue of Nature Neuroscience, could give researchers a new target for drugs to treat these often-intractable conditions.

The discovery, detailed in a study led by neuroscience professor Paul Worley, M.D., of the Johns Hopkins University School of Medicine, focuses on a family of proteins called group 1 metabotropic glutamate receptors (mGluRs) that lie on the surfaces of nerve cells. When these receptors lock in glutamate, a chemical that neurons use to communicate, it encourages neurons to fire.

Without a way to turn off these receptors, neurons would remain active indefinitely, keeping pain and other responses going long after they’re useful. Previous research suggested that these mGluRs need to bind to another protein called Homer to shut down, and that this binding is stronger after other molecules called protein kinases modify the receptors. However, Worley explains, thus far it’s been unclear exactly how all these different players come together.

Seeking the mechanism behind this phenomenon, Worley and his colleagues started with a series of experiments to see what other proteins the mGluRs and Homer were binding with in rat brains. Their search turned up a third protein called Preso1, which bound to both mGluRs and Homer. A search in genetic databases shows that the gene responsible for making Preso1 is present in animals ranging from fruit flies to people, highlighting its importance in a wide variety of creatures.

To figure out what Preso1 does, the researchers performed another series of experiments to examine behavior of neurons that produced both mGluRs and Homer. They found that when these neurons also expressed Preso1, the mGluRs bound Homer more efficiently, suggesting that Preso1 might somehow increase modification by protein kinases.

Worley’s team received another clue when they found that protein kinases also bind to Preso1.

Genetically modifying mice so that they don’t make any Preso1, the researchers found that binding between mGluRs and Homer in these animals’ neurons was greatly reduced compared to normal mice.

Additionally, when the researchers injected the modified mice with a chemical that causes pain and inflammation, the animals had a significantly greater and longer-lasting response compared to regular mice. A final experiment showed that neurons taken from the modified animals were significantly more responsive to the neurotransmitter glutamate. When the researchers added Preso1 to the cell cultures, this increased activity disappeared, suggesting that Preso1 is pivotal for mGluRs to signal properly.

Taken together, Worley explains, the findings suggest that Preso1 appears to gather all the important elements in this system — Homer, protein kinases and mGluRs — bringing them all together to coordinate the activation and deactivation of the mGluRs.

With Preso1 so pivotal for regulating group 1 mGluR activity, it could prove a useful new target for drugs to treat a variety of health problems in which these receptors are thought to play a role, including chronic pain, schizophrenia, Alzheimer’s disease, and fragile X syndrome, Worley says.

"Because mGluRs play so many important roles in the brain for so many different mental and neurological health conditions, knowledge of their regulatory mechanisms is extremely important. But we really don’t know how they work in great detail," he says. "You need to know all the players before you can understand the system. Here, we’ve identified an important player that no one had previously known had existed. Preso1 and Homer appear essential for desensitization of mGluR signaling, much like beta-adrenergic receptor kinase and arrestin are important for desensitization of adrenergic and opiate receptors."

Provided by Johns Hopkins University

Source: medicalxpress.com

July 24, 2012

Einstein’s famous theory of relativity proposed that matter can distort space and time. Now a new study recently published in the journal Neurology suggests that chronic pain can have the same effect.

Neuroscientists from the University of South Australia, Neuroscience Research Australia and the University of Milano Bicocca in Italy, studied people with chronic back pain, the most common painful condition which costs western countries billions of dollars in lost productivity every year.

They presented identical vibration stimuli to the painful area and a non-painful area and noted that the stimuli were processed more slowly by the brain if they came from the painful area.

The most striking finding, however, was that the same effect occurred if the stimuli were delivered to a healthy body part being held near the painful area.

Lead author of the study, Professor Lorimer Moseley from the University of South Australia, says it was not altogether surprising that, in people with chronic pain, there are changes in the way the brain processes information from and about the painful body part.

“But what is remarkable is that the problem affects the space around the body as well as the body itself,” Prof Moseley says.

Experiments showed that if a hand was held near the painful area of the back, the brain would almost ‘neglect’ that hand.

“The potential similarity between our findings and the time-space distortion predicted by the relativity theory is definitely intriguing,” Prof Moseley says.

“Obviously, here it is not external space that is distorted but the ability of the brain to represent that space within its neural circuitry.

“This finding opens up a whole new area of research into the way the brain allows us to interact with the world and how this can be disrupted in chronic pain.”

Provided by University of South Australia

Source: medicalxpress.com

ScienceDaily (July 2, 2012) — There was a time when a belief was widely held that premature neonates did not perceive pain. That, of course, has been refuted but measurements of neonate pain tend to rely on inexact measures, such as alertness and ability to react expressively to pain sensations. Researchers at Loma Linda University reported in The Journal of Pain that there is a significant relationship between procedural pain and detectable oxidative stress in neonates.

Previous studies have shown an approach involving measurement of systemic biochemical reactions to pain offers the benefit of providing an objective method for measuring pain in premature neonates. Exposure to painful procedures often results in reductions in oxygen saturations and tachycardia, but few studies have quantified the effects of increased pain oxygen consumption. No studies have examined the relationship between pain scores that reflect behavioral and physiological markers of pain and plasma markers of ATP utilization and oxidative stress.

In this study, 80 preterm neonates were evaluated. In about half, tape was taken off the skin following removal of catheters, and they were evaluated for oxidative stress by measuring uric acid and malondialdehyde (MDA) concentration in plasma before and after the procedure. These subjects were compared with a control group not experiencing tape removal. Pain scores were assessed using the Premature Infant Pain Profile. The data showed there was a significant relationship between procedural pain and MDA, which is a well accepted marker of oxidative stress.

There were increases in MDA in preterm neonates exposed to the single painful procedure and not in the control group. Since premature neonates undergo several painful procedures a day, the researchers concluded that if exposure to multiple painful procedures is shown to contribute to oxidative stress, biochemical markers might be useful in evaluating mechanism-based interventions that could decrease adverse effects of painful procedures.

Source: Science Daily

ScienceDaily (July 1, 2012) — When people have similar injuries, why do some end up with chronic pain while others recover and are pain free? The first longitudinal brain imaging study to track participants with a new back injury has found the chronic pain is all in their heads — quite literally.

(Credit: © drubig-photo / Fotolia)

A new Northwestern Medicine study shows for the first time that chronic pain develops the more two sections of the brain — related to emotional and motivational behavior — talk to each other. The more they communicate, the greater the chance a patient will develop chronic pain.

The finding provides a new direction for developing therapies to treat intractable pain, which affects 30 to 40 million adults in the United States.

Researchers were able to predict, with 85 percent accuracy at the beginning of the study, which participants would go on to develop chronic pain based on the level of interaction between the frontal cortex and the nucleus accumbens.

The study is published in the journal Nature Neuroscience.

"For the first time we can explain why people who may have the exact same initial pain either go on to recover or develop chronic pain," said A. Vania Apakarian, senior author of the paper and professor of physiology at Northwestern University Feinberg School of Medicine.

"The injury by itself is not enough to explain the ongoing pain. It has to do with the injury combined with the state of the brain. This finding is the culmination of 10 years of our research."

The more emotionally the brain reacts to the initial injury, the more likely the pain will persist after the injury has healed. “It may be that these sections of the brain are more excited to begin with in certain individuals, or there may be genetic and environmental influences that predispose these brain regions to interact at an excitable level,” Apkarian said.

The nucleus accumbens is an important center for teaching the rest of the brain how to evaluate and react to the outside world, Apkarian noted, and this brain region may use the pain signal to teach the rest of the brain to develop chronic pain.

"Now we hope to develop new therapies for treatment based on this finding," Apkarian added.

Chronic pain participants in the study also lost gray matter density, which is likely linked to fewer synaptic connections or neuronal and glial shrinkage, Apkarian said. Brain synapses are essential for communication between neurons.

"Chronic pain is one of the most expensive health care conditions in the U. S. yet there still is not a scientifically validated therapy for this condition," Apkarian said. Chronic pain costs an estimated $600 billion a year, according to a 2011 National Academy of Sciences report. Back pain is the most prevalent chronic pain condition.

A total of 40 participants who had an episode of back pain that lasted four to 16 weeks — but with no prior history of back pain — were studied. All subjects were diagnosed with back pain by a clinician. Brain scans were conducted on each participant at study entry and for three more visits during one year.

Source: Science Daily