Contact: Beth Bukata
American Society for Therapeutic Radiology and Oncology
Internet resources and access remain scarce
Although Spanish-speaking cancer patients are rapidly increasing their search for patient education resources on the Internet, there are very few Spanish-language Web sites available to provide this information, according to a study presented October 28, 2007, at the American Society for Therapeutic Radiology and Oncology’s 49th Annual Meeting in Los Angeles.
Spanish-speaking cancer patients were also shown to have more limited access to the Internet compared to English-speaking users of cancer information Web sites, based on the user patterns of the two groups.
“There is an urgent need for more Web-based information to be more available to Spanish-speaking patients with cancer, and Internet access needs to be more widely available,” said Charles Simone II, M.D., lead author of the study and a radiation oncologist at the Hospital of the University of Pennsylvania in Philadelphia. “The increased knowledge gained among these patients will help to eliminate healthcare disparities and lead to improved medical outcomes.”
The Spanish-language cancer information Web site, OncoLink en español, quadrupled their number of unique visitors last year, from 7,000 visitors per month in January 2006 to nearly 29,000 monthly visitors by the end of the year. More than 200,000 users visited the Web site in 2006.
In contrast, the English-language version of the site, OncoLink, had nearly 2 million visitors last year, although their number of unique visitors did not increase throughout the year. OncoLink en espanõl was launched in 2005 by OncoLink, one of the oldest and largest Internet-based cancer information resources. Both sites are managed by the University of Pennsylvania.
The study shows that OncoLink en español users were less likely to browse the Internet during weekends and morning hours, compared to the users who browsed OncoLink, suggesting that they are accessing the Internet more through work or specialized services.
In addition to when they accessed the Internet, OncoLink en español users also differed on the types of cancers they searched for, as well as the timing and method of their Internet search patterns.
“Awareness of these differences can assist cancer education Web sites to tailor their content to best meet the needs of their Spanish-speaking users,” said Dr. Simone.
The study was carried out using AWStats, a Web-data analyzing program, to collect and compare statistical data from the secure servers of both language versions of OncoLink.
For more information on radiation therapy in English and in Spanish, visit http://www.rtanswers.org.
The abstract, “The Utilization of Radiation Oncology Web-based Resources in Spanish-speaking Oncology Patients,” will be presented for poster viewing starting at 10:00 a.m, Sunday, October 28, 2007. To speak to the study author, Charles Simone, II, M.D, please call Beth Bukata or Nicole Napoli October 28-31, 2007, in the ASTRO Press Room at the Los Angeles Convention Center at 213-743-6222 or 213-743-6223. You may also e-mail them at email@example.com or firstname.lastname@example.org.
Kim SH, Kim DH, Oh DH, Clauw DJ.
Dongguk University College of Medicine, Gyeongju, South Korea, email@example.com.
This blinded study was done to determine if there are any abnormal electron microscopic (EM) findings in the skin of fibromyalgia syndrome (FMS) patients, which might contribute to or be due to the increased pain sensitivity seen in this condition. Skin biopsy samples were obtained from 13 FMS patients and 5 control subjects. All tissues were prepared for EM examination by immediate prefixation in 2.5% glutaraldehyde for 2 h and postfixation in 1% osmium acid for 24 h. Ultrathin sections on grids were stained by uranyl acetate and lead citrate. Biopsies were read by an individual without knowledge of participant status. Five skin biopsies from healthy controls showed relatively even distribution of variegated sized unmyelinated axons sheathed well by complicatedly folded Schwann cell membranes. In tissues from 9/13 FMS patients, unmyelinated Schwann cells were noted to be ballooned, whereas this finding was not noted in any controls (p = 0.029). Axons in most patients trended towards being localized in the periphery of the unmyelinated Schwann cell sheaths (p = 0.002). Particularly, peripheral localization of axon in the unmyelinated Schwann cell sheath had a strong relationship with ballooning of Schwann cell (p = 0.042), simplified folding of Schwann cell sheath (p = 0.039) and smaller axon (p = 0.034). Myelinated nerve fibers were unremarkable. The EM findings seen in the skin of FMS patients show unusual patterns of unmyelinated nerve fibers as well as associated Schwann cells. If these findings are replicated in a larger study, these abnormalities may contribute to, or be due to, the lower pain threshold seen in FMS patients.
Global Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) News.
DID IT HAPPEN IN OUR LONDON?
by Jeanne Hambleton © 2007
This is reported to have happened in London – I don’t think so. Not our London, not the one in the UK with Westminster, Parliament and our new Prime Minister. Not our country where 2% of the population has fibromyalgia – they wouldn’t have the energy to do this. But who knows in these days of PC – politically correctness – anything goes.
This information was sent to me (as a journalist who might be interested) by email and looked like a newspaper cutting. It had no date and very little details about which newspaper this had been published in. It was however written by a reporter named Mike Foster (who I am sure is no relation to Dr Foster who went to Gloucester) who allegedly was writing for the Weekly World News.
The headline intrigued me. It read, “Nine oldsters booted out of nursing home – for trying to have an orgy!”
No it is not our London we don’t have “oldsters”, but I felt I had to read on wondering if it had anything to do with the News of he World, a renowned paper for a bit of juicy gossip. I worked with a former chief reporter of the NoW and he was capable of writing such a story.
The story reported nine “love-hungry” codgers were booted out of an old folks’ home after attempts to organise an orgy in the recreation room. Aged between 73 and 98 the ‘oldsters’ had been planning the late night event for weeks, said the “spokesperson from for the well respected nursing home”. The partygoers were celebrating one woman’s 90th birthday with a sex party.
Contact: Charlotte Webber
The anticipation of a cocaine fix and the actual craving to abuse the drug are two closely related phenomena, according to new evidence published today in the online open access journal Substance Abuse Treatment, Prevention, and Policy.
The study, by Rinah Yamamoto and colleagues at McLean Hospital in Belmont, Massachusetts assessed the suspected link by contrasting reactions to varying perceived availability of the drug. The researchers suggest that more appropriate care could be given if the degree of dependency and abuse were assessed in a natural environment with a potential access to the drug, rather than in a clinical setting.
Yamamoto explains that craving, is an intense and often irrepressible urge to seek and consume the drug, which can result in relapses even after extended periods of abstinence. In searching for effective therapies, understanding how craving, cognition and motivation are entwined is essential.
The researchers administered intravenous cocaine (0.2 mg/kg) to individuals with cocaine dependence who were not seeking treatment. “Unblinded” participants knew for certain they would receive cocaine, while the “blinded” group knew there was a 33 percent chance of getting the drug. The researchers obtained subjective ratings of craving, high, rush and low from the volunteers along with their heart rate and blood pressure measurements. Measurements were collected prior to cocaine administration and every minute for 20 minutes thereafter.
The results showed that several hours prior to the infusion all volunteers had similar craving scores. However, those volunteers who knew they were to receive a cocaine infusion said they felt a greater craving immediately prior to the receipt of cocaine than the “blinded” volunteers who did not know whether the infusion was placebo or the genuine drug. The team also found that the unblinded subjects experienced a more rapid onset of high and rush cocaine responses along with significantly higher cocaine-induced heart rate elevations.
The findings suggest that the cocaine expectancy state modulates the user’s subjective and objective responses to the drug. These data are consistent with the previous studies demonstrating that drug-induced elevated dopamine concentrations in the brain may prime drug users to associate the cues around the source of dopamine boost (e.g., cocaine) with the pleasure experienced once the drug is taken.
Effects of perceived cocaine availability on subjective and objective responses to the drug
Rinah T Yamamoto, Katherine H Karlsgodt, David Rott, Scott E Lukas and Igor Elman
Substance Abuse Treatment, Prevention, and Policy (in press)
During embargo, article available at: http://www.substanceabusepolicy.com/imedia/1803962981502388_article.pdf?random=67240
After the embargo, article available from the journal website at: http://www.substanceabusepolicy.com/
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Please quote the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central’s Open Access policy.
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Global Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) News.
Fibromyalgia syndrome : New developments in pharmacotherapy.
Schwerpunkt Rheumatologie, Sophienblatt 1, 24103, Kiel, Deutschland, email@example.com.
Fibromyalgia syndrome (FMS) affects 2-10% of the adult population in industrial countries and although it is associated with substantial morbidity and disability, treatment options are unsatisfactory. The rapid growth of trials for FMS in recent years has resulted in new, evidence-based approaches to medical treatment. This review focuses on the randomized, controlled studies of newer pharmacological options for FMS, such as selective serotonin/norepinephrine reuptake inhibitors (duloxetine, milnacipran), inhibitors of voltage-gated calcium channels (pregabalin, gabapentin), dopamine-2/3-receptor agonists (pramipexole, ropirinole), sedative-hypnotic agents (sodium oxybate, modafinil, dronabinol), 5-HT3 antagonists (tropisetron) and others (tramadol, dextromethorphan, olanzapine).
Contact: Yivsam Azgad
Weizmann Institute of Science
A group of Israeli scientists from the Technion – Israel Institute of Technology, the Weizmann Institute of Science and Teva Pharmaceutical Industries have recently identified genes responsible for the positive response of many multiple sclerosis patients to the drug Copaxone®. These findings may contribute to the development of personalized medicine for multiple sclerosis sufferers.
Copaxone® was the first original Israeli drug to be approved by the U.S. Food and Drug Administration (FDA), and is today marketed in over 40 countries worldwide, including the U.S.A., Europe, Australia, Latin America and Israel.
The drug molecule was the fruit of research by Prof. Michael Sela, Prof. Ruth Arnon and Dr. Dvora Teitelbaum of the Weizmann Institute’s Immunology Department. It was developed for the treatment of multiple sclerosis (MS) by Teva, which produces and markets Copaxone® today.
‘Until now, medical treatments for all kinds of diseases have relied on trial and error methods to determine dosage and treatment protocols,’ says Prof. Ariel Miller of the Ruth and Bruce Rappaport Faculty of Medicine at the Technion, and Head of the Multiple Sclerosis and Brain Research Center, Carmel Medical Center, Haifa. ‘But the process of fixing the correct dosage affects the efficacy of the treatment and can lead to complications in some cases.’ In the past few years, it has been shown that many drugs are not equally effective for every patient, and this variability is due, at least in part, to genetic differences. Finding medications and doses to suit the genetic make-up of each individual patient is likely to be more successful and to cause fewer side effects.
The new research, which deals with the genetic components of the response to Copaxone®, was recently published in the journal Pharmacogenetics and Genomics. It represents a significant step toward realizing this medical vision. In the collaborative study, Teva supplied DNA samples from drug-treated patients, and the genetic tests were performed at the Crown Human Genome Center of the Weizmann Institute, headed by Prof. Doron Lancet of the Institute’s Department of Molecular Genetics. The scientists used state-of-the-art equipment – the first of its kind in Israel –which allows for the rapid and accurate scanning of variations in the human genome. The scientists then examined the links between the genetic markers they found and the response of MS patients to Copaxone®. They identified several genes that are tied to a positive response to the drug. ‘We analyzed the DNA sequences in 27 candidate genes from each patient participating in the trial,’ said Lancet, ‘and we identified two genes with a high potential for determining the response to Copaxone®. In the future, it may be possible to use this method to scan the genome of MS sufferers, to predict the response levels in advance, and to optimize the dosage and treatment protocol to suit each patient personally.’
Also participating in the research were Prof. Jacques Beckmann (formerly at the Weizmann Institute); Drs. Liat Hayardeny and Dan Goldstaub of Teva; and Iris Grossman, a joint research student at the Technion and the Weizmann Institute.
Copaxone® – Interface between Past and Future
In the 1950’s, Prof. Efraim Katzir of the Weizmann Institute of Science, later fourth president of the State of Israel, commenced research on the properties of proteins – the building blocks of all biological systems. This research led to the design of simple synthetic models of proteins, called ‘polyamino acids.’ His research student at the time, Prof. Michael Sela (who later became President of the Weizmann Institute and was the recipient of, among many honors, the Israel Prize), decided to test the influence of these synthetic molecules on the immune system. This research led him to the conclusion that it might be possible to use these synthetic substances to curb symptoms of multiple sclerosis – an autoimmune disease in which the body’s immune system attacks proteins in the fatty layer surrounding nerve fibers, preventing the conductance of electrical signals through them. Sela, together with his student at the time, Prof. Ruth Arnon (recipient of the Israel Prize and past Vice President of the Weizmann Institute and Vice President of the Association of Academies of Sciences in Asia), and Dr. Dvora Teitelbaum, conducted a long series of experiments. These experiments eventually led to the development of Copaxone®, and clinical trials carried out by Teva showed its efficacy in treating MS. At the end of the process, in 1996, Copaxone® became the first original Israeli drug to be approved by the FDA. Today, following ten years of active sales in the U.S. and 40 countries around the world, Copaxone® has made a significant contribution to the Israeli economy.
Prof. Doron Lancet’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Crown Human Genome Center; and the Laub Fund for Oncogene Research. Prof. Lancet is the incumbent of the Ralph and Lois Silver Professorial Chair in Human Genomics.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il.
Contact: Amelyn Reyes
ROCHESTER, Minn. — Mayo Clinic researchers have found that a human antibody administered in a single low dose in laboratory mouse models can repair myelin, the insulating covering of nerves that when damaged can lead to multiple sclerosis and other disorders of the central nervous system.
The study will be presented on Oct. 9 at the American Neurological Association meeting in Washington, D.C.
“The repair of chronic spinal cord injury is seldom modeled in laboratory studies, but it is an important reality for the treatment of humans. The concept of using natural human antibodies to treat disease of this kind has not yet been tested in humans, but these research findings are very promising,” says Moses Rodriguez, M.D., a Mayo Clinic neurologist and the study’s corresponding author. “The findings could eventually lead to new treatments that could limit permanent disability,” states Arthur Warrington, Ph.D., a Mayo Clinic scientist and study author.
Myelin repair normally occurs spontaneously, but in multiple sclerosis and other disorders of the central nervous system, the myelin repair process occurs very slowly or fails altogether. Researchers are trying to determine how to speed up the myelin healing process, which they hope will eventually lead to new treatments for patients.
The antibody, which was genetically engineered from a single cell, binds to myelin and the surface of cells in the brain and spinal cord, then it triggers the cells to begin the repair process called remyelination. This antibody is the first known reagent designed to induce repair by acting within the central nervous system at the damage sites on cells responsible for myelin synthesis.
The study uses laboratory mouse models of chronic progressive multiple sclerosis in humans. The severity of the disease and also success of the treatment were largely defined by how naturally active the mice were, particularly during the night because mice are nocturnal and are especially active at this time. They received a single dose of the antibody. A minimum of 25 mcg/kg was needed to trigger remyelination, which is equivalent to about 2 mg in the average adult, considered a very low dose. The myelin repair plateaued after five weeks in the mice models.
In addition, when combined with daily methylprednisolone, (an immune modulating steroid) the antibody still promotes remyelination in mouse models. This is an important fact because the first multiple sclerosis patients treated with the antibody will have been treated first with methylprednisolone.
As a naturally occurring protein of the immune system, antibodies do not appear to carry any side effects, nor are they toxic — even when administered at 4,000 times the minimal effective dose — though the concept has not yet been tested in humans, the researchers say.
In summary, this antibody:
Promotes remyelination with a single dose as low as 25 mcg/kg in mice models
The remyelination plateaus at five weeks after a single dose
Converts a model of chronic immune mediated demyelination to one that repairs with the speed of a toxin induced model of demyelination
In terms of replicating the findings in humans, the researchers have already produced the antibody through genetic engineering and conducted preliminary toxicology experiments in mice showing that 1,000 times the therapeutic dose is not toxic. The study continues to be explored in animal models and eventually, in clinical trials.
In short, the critical finding is that when combined with methylprednisolone, the antibody still effectively promotes remyelination and does not make the mice worse, Dr. Warrington states.
About Multiple Sclerosis:
Multiple sclerosis (MS) is a chronic, potentially debilitating disease that affects the central nervous system, which is made up of the brain and spinal cord. Multiple sclerosis is widely believed to be an autoimmune disease, a condition in which the immune system attacks components of the body as if they’re foreign.
Multiple sclerosis affects an estimated 300,000 people in the United States and probably more than 1 million people around the world — including twice as many women as men. Most people experience their first signs or symptoms between ages 20 and 40.
Collaboration and Support
The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, Multiple Sclerosis Society of Canada, the Hilton Foundation and Mr. and Mrs. Eugene Applebaum.
To obtain the latest news releases from Mayo Clinic, go to http://www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories. For more on Mayo Clinic research, go to http://www.mayo.edu.
Contact: Richard Merritt
Duke University Medical Center
DURHAM, N.C. – Long denigrated as vestigial or useless, the appendix now appears to have a reason to be – as a “safe house” for the beneficial bacteria living in the human gut.
Drawing upon a series of observations and experiments, Duke University Medical Center investigators postulate that the beneficial bacteria in the appendix that aid digestion can ride out a bout of diarrhea that completely evacuates the intestines and emerge afterwards to repopulate the gut. Their theory appears online in the Journal of Theoretical Biology.
“While there is no smoking gun, the abundance of circumstantial evidence makes a strong case for the role of the appendix as a place where the good bacteria can live safe and undisturbed until they are needed,” said William Parker, Ph.D., assistant professor of experimental surgery, who conducted the analysis in collaboration with R. Randal Bollinger, M.D., Ph.D., Duke professor emeritus in general surgery.
The appendix is a slender two- to four-inch pouch located near the juncture of the large and small intestines. While its exact function in humans has been debated by physicians, it is known that there is immune system tissue in the appendix.
The gut is populated with different microbes that help the digestive system break down the foods we eat. In return, the gut provides nourishment and safety to the bacteria. Parker now believes that the immune system cells found in the appendix are there to protect, rather than harm, the good bacteria.
For the past ten years, Parker has been studying the interplay of these bacteria in the bowels, and in the process has documented the existence in the bowel of what is known as a biofilm. This thin and delicate layer is an amalgamation of microbes, mucous and immune system molecules living together atop of the lining the intestines.
“Our studies have indicated that the immune system protects and nourishes the colonies of microbes living in the biofilm,” Parkers explained. “By protecting these good microbes, the harmful microbes have no place to locate. We have also shown that biofilms are most pronounced in the appendix and their prevalence decreases moving away from it.”
This new function of the appendix might be envisioned if conditions in the absence of modern health care and sanitation are considered, Parker said.
“Diseases causing severe diarrhea are endemic in countries without modern health and sanitation practices, which often results in the entire contents of the bowels, including the biofilms, being flushed from the body,” Parker said. He added that the appendix’s location and position is such that it is expected to be relatively difficult for anything to enter it as the contents of the bowels are emptied.
“Once the bowel contents have left the body, the good bacteria hidden away in the appendix can emerge and repopulate the lining of the intestine before more harmful bacteria can take up residence,” Parker continued. “In industrialized societies with modern medical care and sanitation practices, the maintenance of a reserve of beneficial bacteria may not be necessary. This is consistent with the observation that removing the appendix in modern societies has no discernable negative effects.”
Several decades ago, scientists suggested that people in industrialized societies might have such a high rate of appendicitis because of the so-called “hygiene hypothesis,” Parker said. This hypothesis posits that people in “hygienic” societies have higher rates of allergy and perhaps autoimmune disease because they — and hence their immune systems — have not been as challenged during everyday life by the host of parasites or other disease-causing organisms commonly found in the environment. So when these immune systems are challenged, they can over-react.
“This over-reactive immune system may lead to the inflammation associated with appendicitis and could lead to the obstruction of the intestines that causes acute appendicitis,” Parker said. “Thus, our modern health care and sanitation practices may account not only for the lack of a need for an appendix in our society, but also for much of the problems caused by the appendix in our society.”
Parker conducted a deductive study because direct examination the appendix’s function would be difficult. Other than humans, the only mammals known to have appendices are rabbits, opossums and wombats, and their appendices are markedly different than the human appendix.
Parker’s overall research into the existence and function of biofilms is supported by the National Institutes of Health. Other Duke members of the team were Andrew Barbas, Errol Bush, and Shu Lin.
Mouse experiments reveal ‘flight or fight’ hormone’s role
Contact: Nick Zagorski
Johns Hopkins Medical Institutions
Both extensive psychological research and personal experiences confirm that events that happen during heightened states of emotion such as fear, anger and joy are far more memorable than less dramatic occurrences. In a report this week in Cell, Johns Hopkins researchers and their collaborators at Cold Spring Harbor and New York University have identified the likely biological basis for this: a hormone released during emotional arousal “primes” nerve cells to remember events by increasing their chemical sensitivity at sites where nerves rewire to form new memory circuits.
Describing the brain as a big circuit board in which each new experience creates a new circuit, Hopkins neuroscience professor Richard Huganir, Ph.D. says that he and his team found that during emotional peaks, the hormone norepinephrine dramatically sensitizes synapses – the site where nerve cells make an electro-chemical connection – to enhance the sculpting of a memory into the big board.
Image showing phosphorylated GluR1 receptors congregating around sites of neuronal synapses.
Norepinephrine, more widely known as a “fight or flight” hormone, energizes the process by adding phosphate molecules to a nerve cell receptor called GluR1. The phosphates help guide the receptors to insert themselves adjacent to a synapse. “Now when the brain needs to form a memory, the nerves have plenty of available receptors to quickly adjust the strength of the connection and lock that memory into place,” Huganir says.
Huganir and his team suspected that GluR1might be a target of norepinephrine since disruptions in this receptor cause spatial memory defects in mice. They tested the idea by either injecting healthy mice with adrenaline or exposing them to fox urine, both of which increase norepinephrine levels in brain. Analyzing brain slices of the mice, the researchers saw increased phosphates on the GluR1 receptors and an increased ability of these receptors to be recruited to synapses.
When the researchers put mice in a cage, gave a mild shock, took them out of that cage and put them back in it the next day, mice who had received adrenaline or fox urine tended to “freeze” in fear – an indicator they associated the cage as the site of a shock – more frequently, suggestive of enhanced memory.
However, in a similar experiment with mice genetically engineered to have a defective GluR1 receptor that phosphates cannot attach to, adrenaline injections had no effect on mouse memory, further evidence of the “priming” effect of the receptor in response to norepinephrine.
The researchers plan on continuing their work by going in the opposite direction and engineering another mouse strain that has a permanently phosphorylated or “primed” receptor. “We’re curious to see how these mice will behave,” Huganir says. “We suspect that they’ll be pretty smart, but at the same time constantly anxious.”
The research was funded by the National Institutes of Health, Damon Runyon Postdoctoral Fellowship, NARSAD, and the Ale Davis and Maxine Harrison Foundation
Authors on the paper are Hailan Hu, Eleonore Real, and Roberto Malinow of Cold Spring Harbor Laboratory; Joe LeDoux of New York University; and Kogo Takamiya, Myoung-Goo Kang, and Huganir of Johns Hopkins
Contact: Alyssa Kneller
Harvard Medical School
BOSTON, Mass. (Oct. 3, 2007)—Imagine an epidural or a shot of Novocain that doesn’t paralyze your legs or make you numb, yet totally blocks your pain. This type of pain management is now within reach. As a result, childbirth, surgery and trips to the dentist might be less traumatic in the future, thanks to researchers at Massachusetts General Hospital (MGH) and Harvard Medical School, who have succeeded in selectively blocking pain-sensing neurons in rats without interfering with other types of neurons.
The pint-sized subjects received injections near their sciatic nerves, which run down their hind limbs, and subsequently lost the ability to feel pain in their paws. But they continued to move normally and react to touch. The injections contained QX-314, a normally inactive derivative of the local anesthetic lidocaine, and capsaicin, the active ingredient in hot peppers. In combination, these chemicals targeted only pain-sensing neurons, preventing them from sending signals to the brain.
“We’ve introduced a local anesthetic selectively into specific populations of neurons,” explains Harvard Medical School Professor Bruce Bean, an author on the paper, which appears in Nature on Oct. 4. “Now we can block the activity of pain-sensing neurons without disrupting other kinds of neurons that control movements or non-painful sensations.”
“We’re optimistic that this method will eventually be applied to humans and change our experience during procedures ranging from knee surgery to tooth extractions,” adds Professor Clifford Woolf of Massachusetts General Hospital, who is senior author on the study.
Despite enormous investments by industry, surgical pain management has changed little since the first successful demonstration of ether general anesthesia at MGH in 1846. General and local anesthetics work by interfering with the excitability of all neurons, not just pain-sensing ones. Thus, these drugs produce dramatic side effects, such as loss of consciousness in the case of general anesthetics or temporary paralysis for local anesthetics.
“We’re offering a targeted approach to pain management that avoids these problems,” says Woolf.
The new work builds on research done since the 1970’s showing how electrical signaling in the nervous system depends on the properties of ion channels, that is, proteins that make pores in the membranes of neurons.
“This project is a perfect illustration of how research trying to understand very basic biological principles can have practical applications,” says Bean.
The new method exploits a membrane-spanning protein called TRPV1, which is unique to pain-sensing neurons. TRPV1 forms a large channel, where molecules can enter and exit the cell. But a “gate” typically blocks this opening. The gate opens when cells are exposed to heat or the chili-pepper ingredient capsaicin. Thus, bathing pain-sensing neurons in capsaicin leaves these channels open, but non-pain sensing neurons are unaffected because they do not possess TRPV1.
The new method then takes advantage of a special property of the lidocaine derivative QX-314. Unlike most local anesthetics, QX-314 can’t penetrate cell membranes to block the excitability of the cell, so it typically lingers outside neurons where it can’t affect them. For this reason it is not used clinically.
When pain-sensing neurons are exposed to capsaicin, however, and the gates guarding the TRPV1 channels disappear, QX-314 can enter the cells and shut them down. But the drug remains outside other types of neurons that do not contain these channels. As a result, these cells fully retain their ability to send and receive signals.
The team first tested their method in the Petri dish. Alexander Binshtok, a postdoctoral researcher in Woolf’s lab, applied capsaicin and QX-314 (separately and in combination) to isolated pain-sensing and other neurons and measured their responses. Indeed, the combination of capsaicin and QX-314 selectively blocked the excitability of pain-sensing neurons, leaving the others unaffected.
Next, Binshtok injected these chemicals into the paws of rats and measured their ability to sense pain by placing them on an uncomfortable heat source. The critters tolerated much more heat than usual. He then injected the chemicals near the sciatic nerve of the animals and pricked their paws with stiff nylon probes. The animals ignored the provocation. Although the rats seemed immune to pain, they continued to move normally and respond to other stimuli, indicating that QX-314 failed to penetrate their motor neurons.
The team must overcome several hurdles before this method can be applied to humans. They must figure out how to open the TRPV1 channels without producing even a transient burning pain before QX-314 enters and blocks the neurons, and they must tinker with the formulation to prolong the effects of the drugs. Both Bean and Woolf are confident they’ll succeed.
“Eventually this method could completely transform surgical and post-surgical analgesia, allowing patients to remain fully alert without experiencing pain or paralysis,” says Woolf. “In fact, the possibilities seem endless. I could even imagine using this method to treat itch, as itch-sensitive neurons fall into the same group as pain-sensing ones.”
Research in the Woolf lab is supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Dental and Craniofacial Research. Research in the Bean lab is supported by NINDS and the National Institute of General Medical Sciences.
Harvard and MGH have filed patents on this technology platform.
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