Posts tagged pain

October 6, 2014

Pain words stand out more for those experiencing it

Ache, agony, distress and pain draw more attention than non-pain related words when it comes to people who suffer from chronic pain, a York University research using state-of-the-art eye-tracking technology has found.

(Image credit)

“People suffering from chronic pain pay more frequent and longer attention to pain-related words than individuals who are pain-free,” says Samantha Fashler, a PhD candidate in the Faculty of Health and the lead author of the study. “Our eye movements — the things we look at — generally reflect what we attend to, and knowing how and what people pay attention to can be helpful in determining who develops chronic pain.”

Chronic pain currently affects about 20 per cent of the population in Canada.

The current study, “More than meets the eye: visual attention biases in individuals reporting chronic pain”, published in the Journal of Pain Research, incorporated an eye-tracker, which is a more sophisticated measuring tool to test reaction time than the previously used dot-probe task in similar studies.

“The use of an eye-tracker opens up a number of previously unavailable avenues for research to more directly tap what people with chronic pain attend to and how this attention may influence the presence of pain,” says Professor Joel Katz, Canada Research Chair in Health Psychology, the co-author of the study.

The researchers recorded both reaction time and eye movements of chronic pain (51) and pain-free (62) participants. Both groups viewed neutral and sensory pain-related words on a dot-probe task. They found reaction time did not indicate attention, but “the eye-tracking technology captured eye gaze patterns with millimetre precision,” according to Fashler. She points out that this helped researchers to determine how frequently and how long individuals looked at sensory pain words.

“We now know that people with and without chronic pain differ in terms of how, where and when they attend to pain-related words. This is a first step in identifying whether the attentional bias is involved in making pain more intense or more salient to the person in pain,” says Katz.

(Source: news.yorku.ca)

Filed under pain chronic pain eye-tracking technology attention psychology neuroscience science

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October 3, 2014

New study finds link between depression and abnormal brain response to visceral pain in patients with IBS

At the 22^nd United European Gastroenterology Week (UEG Week 2014) in Vienna, Austria, Professor Sigrid Elsenbruch from the University of Duisburg-Essen in Germany, will be presenting a new study which suggests that depression, but not anxiety, contributes to the abnormal pain processing observed in IBS in a model that addresses central pain inhibition during placebo analgesia. “Our study has shown that patients with IBS are less able to suppress pain signals in the brain coming from the bowel and that depression plays a role herein,” she says. “This study confirms the complex relationship between the gut and the brain and shows that affective disorders may contribute to the development or maintenance of disturbed pain processing in IBS.”

IBS, anxiety and depression

IBS is the most common functional gastrointestinal disorder with prevalence rates of up to 23% reported. The condition is characterised by recurrent abdominal pain or discomfort, in combination with bloating and altered bowel habits (e.g. diarrhoea and/or constipation). Depression and anxiety frequently co-exist with IBS, with a recent study reporting that 38% of IBS patients had clinically-confirmed depression (compared with 6% of healthy controls) and 32% had anxiety (compared with 13% of healthy controls).

“The fact that so many people with IBS have anxiety and depression has led many to speculate that IBS is primarily a psychological, not a physical, disorder,” says Prof. Elsenbruch. “However, the condition is complex and most likely results from an interplay between psychological and biological factors. In fact, we don’t really know whether anxiety and depression result from having IBS or whether they contribute to the development or maintenance of symptoms. In many patients, both possibilities may be true at the same time.”

The “brain–gut” axis in IBS

There has been significant scientific interest in the role of central nervous system mechanisms along the “brain–gut” axis in IBS. Neuroimaging studies have demonstrated that neural processing of visceral stimuli (i.e. stimuli generated from internal organs such as the intestine) is altered in IBS, with many IBS patients showing lowered pain thresholds. In Prof. Elsenbruch’s latest study, painful rectal distensions were performed using a pressure-controlled barostat system in 17 patients with IBS and 17 sex- and age-matched healthy controls. Neural activation in pain-related brain areas was assessed using functional MRI (fMRI) while subjects received sequential intravenous administrations of saline and what they thought was an anti-spasmolytic drug (but was actually a saline placebo), in order to observe activation patterns during a typical placebo pain response.

The fMRI results in the healthy volunteers demonstrated reduced neural activation in pain-related brain areas during both the saline and sham treatment (placebo), indicating significant central pain inhibition. However, there was no such inhibition in the group of IBS patients, suggesting a deficiency in central pain inhibitory mechanisms in IBS. Interestingly, higher depression (but not anxiety) scores on the Hospital Anxiety and Depression Scale (HADS) were associated with reduced central pain inhibition in this study.

“Our findings suggest that patients with IBS do not process visceral pain signals in the same way as healthy people and are unable to suppress pain signals in the brain and, as a result, experience more pain from the same stimuli,” says Prof. Elsenbruch. “The fact that the presence of depression was associated with altered brain responses suggests that depression may contribute to these abnormal pain processes in IBS patients.”

Filed under irritable bowel syndrome depression placebo analgesia pain neuroscience science

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October 2, 2014

Medical discovery first step on path to new painkillers

A major medical discovery by scientists at The University of Nottingham could lead to the development of an entirely new type of painkiller.

A drug resulting from the research, published in the journal Neurobiology of Disease, would offer new hope to sufferers of chronic pain conditions such as traumatic nerve injury, for which few effective painkillers are currently available.

The work, led by Dr Lucy Donaldson in the University’s School of Life Sciences, in collaboration with David Bates, Professor of Oncology in the University’sCancer Biology Unit, focuses on a signal protein called vascular endothelial growth factor (VEGF).

VEGF controls the re-growth of blood vessels in tissues which have been damaged by injury. It is a widely targeted compound for cancer, eye disease and other illnesses in which abnormal blood vessel growth occurs.

Drugs are used to inhibit the VEGF in cancer, which can otherwise lead to the formation of new blood vessels that provide oxygen and nutrients to tumours.

Professor Bates and colleagues had previously discovered in 2002 that VEGF comes in two forms and acts like a switch — one which turns on the growth of blood vessels and another that blocks growth.

Pain prevention

However, this latest research has shown for the first time that these two forms of VEGF not only act on blood vessels but also differently affect the sensory nerves that control pain.

The academics discovered that the VEGF that promotes blood vessel growth causes pain, while the other, which inhibits blood vessel growth, prevents pain.

The study has centred on understanding how these two types of VEGF work and why the body makes one form rather than the other.

The academics have been able to switch from the pain stimulating form to the pain inhibiting VEGF in animal models in the laboratory and are now investigating compounds to replicate this in humans. It is thought these compounds could form the basis for new drugs to be tested in humans in clinical trials.

Filed under neuropathy pain painkiller VEGF medicine science

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September 4, 2014

Researchers unlock new mechanism in pain management

It’s in the brain where we perceive the unpleasant sensations of pain, and researchers have long been examining how calcium channels in the brain and peripheral nervous system contribute to the development of chronic pain conditions.

Neuroscientist Gerald Zamponi, PhD, and his team at the University of Calgary’s Hotchkiss Brain Institute have discovered a new mechanism that can reverse chronic pain. Using an animal model, their research has found that pain signals in nerve cells can be shut off by interfering with the communication of a specific enzyme with calcium channels, a group of important proteins that control nerve impulses.

Their Canadian Institutes of Health Research-funded study was published in the September issue of Neuron — one of the most influential journals in the field of neuroscience.

Zamponi is now applying his research and partnering with the Centre for Drug Research and Development (CDRD) in Vancouver to develop a drug that could one day improve the lives of those with inflammatory pain such as arthritis, irritable bowel disease or neuropathic pain. Their approach may be able to reduce the pain associated with these conditions.

Opening the door to new treatments

“Chronic pain can be a debilitating condition that affects many people and is often poorly controlled by currently available treatments. Therefore, new treatment avenues are needed. Our discovery opens the door towards new treatments, and based on the data that we have so far, it is a viable strategy,” says Zamponi, the lead author of the study and senior associate dean of research at the Cumming School of Medicine.

With CDRD, Zamponi and his team are screening more than 100,000 molecules in hopes of finding one that would stop the enzyme from communicating with the calcium channel. If they can isolate the right molecule, they can potentially turn it into a drug. So far, they have already found two viable molecules that have been validated by his group as painkillers in animals.

Promising innovation from basic research

Commercialization of the project Zamponi and his team are working on is one of six funded through the competition of the Alberta/Pfizer Translational Research Fund Opportunity. “AIHS is delighted that the strong partnership created with Pfizer, Western Economic Diversification, and Alberta Innovation and Advanced Education is helping to develop promising innovations from basic research into technologies, drugs, and tools to improve health,” says Dr. Cy Frank, president and CEO of Alberta Innovates – Health Solutions.

The Alberta/Pfizer Translational Research Fund Opportunity is a partnership between Pfizer Canada Inc., Alberta Innovates – Health Solutions, Alberta’s Ministry of Innovation and Advanced Education, and Western Economic Diversification Canada. This partnership will provide opportunities to focus on the development and commercialization of innovations in health. More than $3.25 million has been committed to identify and support promising health-care innovations with market potential.

Filed under pain chronic pain USP5 calcium channel neuroscience science

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September 3, 2014

(Image caption: A consensus shape for the calcium ion channel in the worm’s pain receptor nerve that was reached by computer modeling. Credit: Damian van Rossum and Andriy Anishkin, Duke University)

Surprising New Role for Calcium in Sensing Pain

When you accidentally touch a hot oven, you rapidly pull your hand away. Although scientists know the basic neural circuits involved in sensing and responding to such painful stimuli, they are still sorting out the molecular players.

Duke researchers have made a surprising discovery about the role of a key molecule involved in pain in worms, and have built a structural model of the molecule. These discoveries, described Sept. 2 in Nature Communications, may help direct new strategies to treat pain in people.

In humans and other mammals, a family of molecules called TRP ion channels plays a crucial role in nerve cells that directly sense painful stimuli. Researchers are now blocking these channels in clinical trials to evaluate this as a possible treatment for various types of pain.

The roundworm Caenorhabditis elegans also expresses TRP channels — one of which is called OSM-9 — in its single head pain-sensing neuron (which is similar to the pain-sensing nerve cells for the human face). OSM-9 is not only vital for detecting danger signals in the tiny worms, but is also a functional match to TRPV4, a mammalian TRP channel involved in sensing pain.

In the new study, researchers created a series of genetic mutant worms in which parts of the OSM-9 channel were disabled or replaced and then tested the engineered worms’ reactions to overly salty solution, which is normally aversive and painful.

Specifically, the mutant worms had alterations in the pore of the OSM-9 channels in their pain-sensing neuron, which gets fired up upon channel activation to allow calcium and sodium to flow into the neuron. That, in turn, was thought to switch on the neural circuit that encodes rapid withdrawal behavior — like pulling the finger from the stove.

“People strongly believed that calcium entering the cell through the TRP channel is everything in terms of cellular activation,” said lead author Wolfgang Liedtke, M.D., Ph.D., an associate professor of neurology, anesthesiology and neurobiology at Duke University School of Medicine and an attending physician in the Duke Pain Clinics, where he sees patients with chronic head-neck and face-pain.

With then-graduate student Amanda Lindy, “we wanted to systemically mutagenize the OSM-9 pore and see what we could find in the live animal, in its pain behavior,” Liedtke said.

To the group’s surprise, changing various bits of OSM-9’s pore did not change most of the mutant worms’ reactions to the salty solution. However, these mutations did affect the flow of calcium into the cell. The disconnect they saw suggested the calcium was not playing a direct role in the worms’ avoidance of danger signals.

Calcium has been thought to be indispensable for pain behavior — not only in worms’ channels but in pain-related TRP channels in mammals. So results from the engineered OSM-9 mutant worms will change a central concept for the understanding of pain, Liedtke said.

To see whether calcium might instead play a role in the worms’ ability to adapt to repeated painful stimuli, the group then repeatedly exposed pore-mutant worms to the aversive and pain stimuli.

After the tenth trial, a normal worm becomes less sensitive to high salt. But one mutant worm with a minimal change to one specific part of its OSM-9 pore — altered so that calcium no longer entered but sodium did — was just as sensitive on the tenth trial as on the first.

The results confirmed that calcium flow through the channel makes the worms more adaptable to painful stimuli; it helps them cope with the onslaught by desensitizing them. This could well represent a survival advantage, Liedtke said.

To put the findings into a structural context, Liedtke collaborated with computational protein scientists Damian van Rossum and Andriy Anishkin from Penn State University, who built a structural model of OSM-9 that was based on established structures of several of the channel’s relatives, including the recently resolved structure of TRPV1, the molecule that senses pain caused by heat and hot chili peppers.

The team was then able to visualize the key parts of the OSM-9 pore in the context of the entire channel. They understood better how the pore holds its shape and allows sodium and calcium to pass.

Liedtke said that understanding this structure could be a great help in designing compounds that will not completely block the channel but will just prevent calcium from entering the cell. Although calcium helps desensitize worms to painful stimuli in the near term, it might set up chronic, pathological pain circuits in the long term, Liedtke said.

So, as a next step, the group plans to assess the longer-term effects calcium flow has in pain neurons. For example, calcium could change the expression of particular genes in the sensory neuron. And such gene expression changes could underlie chronic, pathologic pain.

“We assume, and so far the evidence is quite good, that chronic, pathological pain has to do with people’s genetic switches in their sensory system set in the wrong way, long term. That’s something our new worm model will now allow us to approach rationally by experimentation,” Liedtke said.

Filed under pain ion channels calcium influx C. elegans neurons neuroscience science

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August 10, 2014

The future of pain relief?

Dutch burns unit trialling new virtual reality computer system that distracts patients from the agony of their wounds

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August 2, 2014

Study reveals brain mechanism behind chronic pain’s sapping of motivation

Chronic pain is among the most abundant of all medical afflictions in the developed world. It differs from a short-term episode of pain not only in its duration, but also in triggering in its sufferers a psychic exhaustion best described by the question, “Why bother?”

A new study in mice, conducted by investigators at the Stanford University School of Medicine, has identified a set of changes in key parts of the brain that may explain chronic pain’s capacity to stifle motivation. The discovery could lead to entirely new classes of treatment for this damaging psychological consequence of chronic pain.

Many tens of millions of people in the United States suffer persistent pain due to diverse problems including migraines, arthritis, lower back pain, sports injuries, irritable bowel syndrome and shingles. For many of these conditions, there are no good treatments, and a crippling loss of mojo can result.

“With chronic pain, your whole life changes in a way that doesn’t happen with acute pain,” said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences and the study’s senior author. “Yet this absence of motivation caused by chronic pain, which can continue even when the pain is transiently relieved, has been largely ignored by medical science.”

A series of experiments in mice by Malenka and his colleagues, described in a study published Aug. 1 in Science, showed that persistent pain causes changes in a set of nerve cells in a deep-brain structure known to be important in reward-seeking behavior: the pursuit of goals likely to yield pleasurable results. Malenka’s lab has been studying this brain structure, the nucleus accumbens, for two decades.

“We showed that those brain changes don’t go away when you transiently relieve the mice’s pain,” Malenka said. The experiments also indicated that the mice’s diminished motivation to perform reward-generating tasks didn’t stem from their pain’s rendering them incapable of experiencing pleasure or from any accompanying physical impairment, he said.

How pain and reward interact

“This study is important — to my knowledge, the first to explain how pain and reward interact. It begins to get to an understanding of why it’s such a struggle for people undergoing chronic pain to get through the day,” said Howard Fields, MD, PhD, a professor of neurology at the University of California-San Francisco and founder of that school’s pain management center.

Fields, who did not participate in the Malenka group’s study but wrote an accompanying perspective piece published simultaneously in Science, described the psychological effect of chronic pain as “the clouding of the future. There’s no escape from it. You want it to end, but it doesn’t.” As a result, people become pessimistic and irritable, he said. “People come to expect the next day is going to wind up being painful. It just takes the edge off of life’s little pleasures — and big pleasures, for that matter.”

The experiments were spearheaded by the study’s first author, Neil Schwartz, PhD, a postdoctoral scholar in Malenka’s lab. “You can’t just ask a hungry mouse how motivated it is to pursue its heart’s desire,” Malenka said. “But there are ways of asking that mouse, ‘How hard are you willing to work for food?’”

Schwartz, Malenka and their associates looked at lab mice enduring chronic paw pain due either to persistent inflammation or to nerve damage. The mice also happened to be hungry. The scientists trained the mice to poke their noses into a hole to get a food pellet. At first, a single nose poke earned a pellet. But over time, the number of nose pokes required for a reward was increased. In essence, the researchers were asking these mice: How hard are you willing to work for food? Will you poke your nose into that hole once to satisfy your hunger? Ten times? Even 150 times?

Fading motivation

Within a week after the onset of chronic pain, the animals grew increasingly less likely to work hard for food than pain-free control animals were. The researchers next explored three possible explanations: Were the mice unable to work because their pain was too severe? Did something about being in pain cause them to not value the food reward as much? Or was their failure to seek food due simply to a lack of motivation? Additional tests showed that the mice had no movement problems. “Like other research groups, we found that they can scamper around just fine,” said Malenka. Also, when the mice were given free access to food, they ate just as much as the animals who weren’t in pain — so they still valued the food. But they were less willing to put in an effort to obtain food than mice who’d suffered no pain.

Moreover, the difference didn’t disappear even when the scientists relieved the mice’s pain with analgesics. “They were in demonstrably less pain, but they were still less willing to work,” Malenka said.

The Stanford scientists then focused on the nucleus accumbens, a brain structure known to be involved in computing the behavioral strategies that prompt us to seek or avoid things that can affect our survival. They found that chronic pain permanently changed certain connections to the nucleus accumbens, causing an enduring downshift in the excitation transmitted by them. Importantly, Malenka’s group showed that a particular brain chemical called galanin plays a critical role in this enduring suppression of nucleus accumbens excitability.

Galanin is a short signaling-protein snippet secreted by certain cells in various places in the brain. While its presence in the brain has been known for a good 60 years or so, galanin’s role is not well-defined and probably differs widely in different brain structures. There have been hints, though, that galanin activity might play a role in pain. For example, it’s been previously shown in animal models that galanin levels in the brain increase with the persistence of pain.

Possible therapies?

Schwartz, Malenka and their peers identified receptors for galanin on a set of nerve cells in the nucleus accumbens and demonstrated that disabling galanin’s signaling via this receptor prevented the long-term suppression of motivation seen in mice — and people — with chronic pain. This suggests that therapeutic compounds with similar effects could someday be developed, although they would have to be carefully targeted so as to not disrupt galanin signaling in other important brain circuits.

“There’s no reason to think this finding won’t generalize to people,” said Fields of UCSF. “Our brains have galanin, and a nucleus accumbens, just as mouse brains do. However, before jumping from mice to humans it would be wise to test other animal species. If the same things happen in a non-rodent species that happen in mice, then it’s probable they happen in humans, too.”

(Source: med.stanford.edu)

Filed under pain chronic pain motivation reward nucleus accumbens neuroscience science

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July 11, 2014

New research: teaching the brain to reduce pain

People can be conditioned to feel less pain when they hear a neutral sound, new research from the University of Luxembourg has found. This lends weight to the idea that we can learn to use mind-over-matter to beat pain. The scientific article was published recently in the online journal “PLOS One”.

Scientists have known for many years that on-going pain in one part of the body is reduced when a new pain is inflicted to another part of the body. This pain blocking is a physiological reaction by the nervous system to help the body deal with a potentially more relevant novel threat.

To explore this “pain inhibits pain” phenomenon, painful electric pulses were first administered to a subject’s foot (first pain) and the resulting pain intensity was then measured. Then the subject was asked to put their hand in a bucket of ice water (novel stimulus causing pain reduction), and as they did so, a telephone ringtone sounded in headphones. After this procedure had been repeated several times, it was observed that the pain felt from the electrical stimulation was reduced simply when the ring tone sounded.

The brain had been conditioned to the ringtone being a signal to trigger the body’s physical pain blocking mechanism. The people being tested not only felt significantly less pain, but there were also fewer objective signs of pain, such as activity in the muscles used in the facial expression of pain (frowning). In total, 32 people were tested.

“We have shown that just as the physiological reaction of saliva secretion was provoked in Pavlov’s dogs by the ringing of a bell, an analogous effect occurs regarding the ability to mask pain in humans,” said Fernand Anton, Professor of Biological Psychology at the University of Luxembourg. “Conversely, similar learning effects may be involved in the enhancement and maintenance of pain in some patients,” added Raymonde Scheuren, lead researcher in this study.

Filed under pain learning pavlovian conditioning electrical stimulation neuroscience science

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June 7, 2014

‘Map of pain’ reveals how our ability to identify the source of pain varies across the body

“Where does it hurt?” is the first question asked to any person in pain.

A new UCL study defines for the first time how our ability to identify where it hurts, called “spatial acuity”, varies across the body, being most sensitive at the forehead and fingertips.

Using lasers to cause pain to 26 healthy volunteers without any touch, the researchers produced the first systematic map of how acuity for pain is distributed across the body. The work is published in the journal Annals of Neurology and was funded by the Wellcome Trust.

With the exception of the hairless skin on the hands, spatial acuity improves towards the centre of the body whereas the acuity for touch is best at the extremities. This spatial pattern was highly consistent across all participants.

The experiment was also conducted on a rare patient lacking a sense of touch, but who normally feels pain. The results for this patient were consistent with those for healthy volunteers, proving that acuity for pain does not require a functioning sense of touch.

“Acuity for touch has been known for more than a century, and tested daily in neurology to assess the state of sensory nerves on the body. It is striking that until now nobody had done the same for pain,” says lead author Dr Flavia Mancini of the UCL Institute of Cognitive Neuroscience. “If you try to test pain with a physical object like a needle, you are also stimulating touch. This clouds the results, like taking an eye test wearing sunglasses. Using a specially-calibrated laser, we stimulate only the pain nerves in the upper layer of skin and not the deeper cells that sense touch.”

Volunteers were blindfolded and had specially-calibrated pairs of lasers targeted at various parts of their body. These lasers cause a brief sensation of pinprick pain. Sometimes only one laser would be activated, and sometimes both would be, unknown to participants. They were asked whether they felt one ‘sting’ or two, at varying distances between the two beams. The researchers recorded the minimum distance between the beams at which people were able to accurately say whether it was one sting or two.

“This measure tells us how precisely people can locate the source of pain on different parts of their body,” explains senior author Dr Giandomenico Iannetti of the UCL Department of Neuroscience, Physiology and Pharmacology. “Touch and pain are mediated by different sensory systems. While tactile acuity has been well studied, pain acuity has been largely ignored, beyond the common textbook assertion that pain has lower acuity than touch. We found the opposite: acuity for touch and pain are actually very similar. The main difference is in their gradients across the body. For example, pain acuity across the arm is much higher at the shoulder than at the wrist, whereas the opposite is true for touch.”

Acuity for both touch and pain normally correlates with the density of the relevant nerve fibres in each part of the body. However, the fingertips remain highly sensitive despite having a low density of pain-sensing nerve cells.

“The high pain acuity of the fingertips is something of a mystery that requires further investigation,” says Dr Mancini. “This may be because people regularly use their fingertips, and so the central nervous system may learn to process the information accurately.”

The findings have important implications for the assessment of both acute and chronic pain. Dr Roman Cregg of the UCL Centre for Anaesthesia, who was not involved in the research, is a clinical expert who treats patients with chronic pain.

“Chronic pain affects around 10 million people in the UK each year according to the British Pain Society, but we still have no reliable, reproducible way to test patients’ pain acuity,” says Dr Cregg. “This method offers an exciting, non-invasive way to test the state of pain networks across the body. Chronic pain is often caused by damaged nerves, but this is incredibly difficult to monitor and to treat. The laser method may enable us to monitor nerve damage across the body, offering a quantitative way to see if a condition is getting better or worse. I am excited at the prospect of taking this into the clinic, and now hope to work with Drs Mancini and Iannetti to translate their study to the chronic pain setting.”

(Source: ucl.ac.uk)

Filed under spatial acuity touch pain neuroscience science

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May 23, 2014

Blocking pain receptors extends lifespan, boosts metabolism in mice

Blocking a pain receptor in mice not only extends their lifespan, it also gives them a more youthful metabolism, including an improved insulin response that allows them to deal better with high blood sugar.

"We think that blocking this pain receptor and pathway could be very, very useful not only for relieving pain, but for improving lifespan and metabolic health, and in particular for treating diabetes and obesity in humans," said Andrew Dillin, a professor of molecular and cell biology at the University of California, Berkeley, and senior author of a new paper describing these results. "As humans age they report a higher incidence of pain, suggesting that pain might drive the aging process."

The “hot” compound in chili peppers, capsaicin, is already known to activate this pain receptor, called TRPV1 (transient receptor potential cation channel subfamily V member 1). In fact, TRPV1 is often called the capsaicin receptor. Constant activation of the receptor on a nerve cell results in death of the neuron, mimicking loss of TRPV1, which could explain why diets rich in capsaicin have been linked to a lower incidence of diabetes and metabolic problems in humans.

More relevant therapeutically, however, is an anti-migraine drug already on the market that inhibits a protein called CGRP that is triggered by TRPV1, producing an effect similar to that caused by blocking TRPV1. Dillin showed that giving this drug to older mice restored their metabolic health to that of younger mice.

"Our findings suggest that pharmacological manipulation of TRPV1 and CGRP may improve metabolic health and longevity," said Dillin, who is a Howard Hughes Medical Institute investigator and the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research. "Alternatively, chronic ingestion of compounds that affect TRPV1 might help prevent metabolic decline with age and lead to increased longevity in humans."

Dillin and his colleagues at UC Berkeley and The Salk Institute for Biological Studies in La Jolla, Calif., will publish their results in the May 22 issue of the journal Cell.

Pain and obesity

TRPV1 is a receptor found in the skin, nerves and joints that reacts to extremely high temperatures and other painful stimuli. The receptor is also found in nerve fibers that contact the pancreas, where it stimulates the release of substances that cause inflammation or, like CGRP (calcitonin gene-related peptide), prevent insulin release. Insulin promotes the uptake of sugar from the blood and storage in the body’s tissue, including fat.

Past research has shown that mice lacking TRPV1 are protected against diet-induced obesity, suggesting that this receptor plays a role in metabolism. Disrupting sensory perception also increases longevity in worms and flies. But until now, it was not known whether sensory perception also affects aging in mammals.

Dillin and his team have now found that mice genetically manipulated to lack TRPV1 receptors lived, on average, nearly four months – or about 14 percent – longer than normal mice. The TRPV1-deficient mice also showed signs of a youthful metabolism late in life, due to low levels of CGRP — a molecule that blocks insulin release resulting in increased blood glucose levels and thus could contribute to the development of type 2 diabetes. Throughout aging, these mice showed improved ability to quickly clear sugar from the blood as well as signs that they could burn more calories without increasing exercise levels.

Moreover, old mice treated with the anti-migraine drug, which inhibits the activity of CGRP receptors, showed a more youthful metabolic profile than untreated old mice.

UC Berkeley and The Salk Institute filed a patent May 16 on the technology described in the Cell paper. Dillin plans to continue his studies of the effects of TRPV1 and CGRP blockers on mice and, if possible, humans.

(Source: eurekalert.org)

Filed under TRPV1 pain pain receptors longevity lifespan obesity neuroscience science