Fruit flies lead scientists to new human pain gene

While it has become clear in recent years that susceptibility to pain has a strong inherited component, very little is known about actual "pain genes" and how they work. In the November 12th issue of Cell, researchers at Children's Hospital Boston and their collaborators report on a novel human pain gene. People with minor variations in this gene showed clear differences in susceptibility to acute heat pain and chronic back pain. Corroborating mouse studies give some clues as to how the gene controls pain sensitivity. The gene was uncovered in a genome-wide hunt for pain genes in fruit flies, which revealed hundreds of other candidate pain genes that await further study.

Understanding the genetic basis of pain will lead to the development of new analgesics, the identification of risk factors for chronic pain and improved decision-making about the suitability of surgical treatment for different patients, says Clifford Woolf, MB, BCh, PhD, the study's senior co-author and director of the F.M. Kirby Center and Program in Neurobiology at Children's.

Classic studies of twins indicate that about 50 percent of variance in pain sensitivity is inherited. "Across a number of different kinds of pain, genes seem to be at least half the driver of how much pain you experience," Woolf says. "Genes give us an amazing and powerful tool to begin to understand how pain is generated, and which functional pathways and specific proteins are involved."

The new gene, discovered in a collaboration with the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and others, encodes part of a calcium channel called alpha 2 delta 3 (α2δ3). Calcium channels are pores in the cell membrane through which calcium ions pass, and are critical for the electrical excitability of nerve cells.

The study, co-led by Joseph Penninger, PhD, scientific director of the Institute of Molecular Biotechnology in Vienna, took advantage of the relative ease of conducting genetic screens in fruit flies. Nearly 12,000 genes were targeted for mutations specifically in nerve cells, using RNA interference (RNAi) technology. The team then exposed the different mutant flies to noxious heat, and identified the ones that failed to fly away. After eliminating flies with other complications, such as an inability to see or fly, they zeroed in on those with mutations that appeared to be specific to pain.

Of the nearly 600 candidate pain genes identified, α2δ3 was one chosen for further study, in part because calcium channels are a known target of some existing analgesics. (Another member of the α2δ family of calcium channels, α2δ1, is a target of gabapentin and pregablin, commonly prescribed for neuropathic pain.)

Studies of mice lacking α2δ3 demonstrated that this gene controls sensitivity to noxious heat in mammals as well as flies. Further, functional MRI imaging of the mutant mice revealed that α2δ3 controls the processing of thermal pain signals in the brain: the heat pain signal seems to arrive appropriately at the thalamus, an early processing center, but does not travel to higher order pain centers in the cortex. Instead, the MRI images showed a surprising cross-activation of vision, olfaction and hearing cortical areas. This cross-activation, or synesthesia, was noted with tactile stimulation in addition to the heat pain stimulus.

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http://www.labspaces.net/107635/Fruit_flies_lead_scientists_to_new_human_pain_gene

How Pain Can Make You Feel Better: Scientific American

What do you do when you're stressed out? Talk to friends? Listen to music? Have a drink, or eat some ice cream? Or maybe practice yoga? These things are all pleasant options, and they're obvious, effective ways to deal with stress. Chances are that you would not even think about doing something like, say, cutting your arm with a knife until you draw blood. Yet inflicting pain is exactly what millions of Americans – particularly adolescents and young adults – do to themselves when they're stressed.

This is called nonsuicidal self-injury (NSSI), and it most commonly takes the form of cutting or burning the skin. Traditionally, many doctors, therapists, and family members have believed that people engage in NSSI primarily to manipulate others. However, recent research has found that such social factors only motivate a minority of cases and usually represent cries for help rather than coldhearted attempts to exploit caretakers. Although there are many reasons why people engage in this kind of self-injury, the most commonly reported reason is simple, if seemingly odd: to feel better. Several studies support the claim that self-inflicted pain can lead to feeling better. For example, Schmahl and colleagues scanned the brains of people with a history of NSSI during a painful experimental task designed to mimic NSSI. They found that the pain led to decreased activity in the areas of the brain associated with negative emotion. The reality of this effect provokes a perplexing question: How could self-inflicted pain possibly lead to feeling better?

One possible answer to this question is that some people are simply hard-wired to like pain. Although NSSI is associated with an increased pain threshold and tolerance, people who engage in NSSI still report feeling pain and, furthermore, report that this pain is unpleasant. Moreover, if these people are hard-wired to like pain, it is unclear why they primarily engage in NSSI when stressed or why they stick to moderate self-injury (e.g., cutting the skin) rather than severe self-injury (e.g., limb amputation).

Another possible answer is that these people want to punish themselves and that they simply like punishment. It is true that self-punishment is a commonly reported reason for engaging in NSSI; however, by definition, punishments increase negative emotion and make a behavior less likely to occur in the future. Thus, self-punishment may motivate some of these people, but self-punishment cannot be the reason that NSSI reduces bad feelings. During NSSI, something else must accompany the negative emotion associated with self-punishment and pain. Exciting new research now suggests that this "something else" is the relief that occurs when something that causes acute, intense pain is removed.

To illustrate this effect, imagine that one morning you visit the doctor for a routine check-up, and later that afternoon the doctor's office calls to inform you that you're in the advanced stages of cancer and have weeks to live.... Now imagine that the doctor's office calls back five minutes later and tells you that they mixed up your lab work with someone else's – you're actually in good health. You would not immediately go back to how you felt before the first phone call; rather, you would feel extreme relief, lasting for hours or even days. Note that it was not a reward (e.g., winning the lottery) that made you feel better, only the introduction and removal of something unpleasant.

New research suggests that the introduction and removal of physical pain may have a similar effect. Tanimoto and colleagues found that fruitflies avoided odors associated with the introduction of a shock, but approached odors associated with the removal of a shock. Similarly, Bresin and colleagues found that the removal various forms of experimental pain were associated with a reduction in negative emotion in people with no history of NSSI. This relief effect was particularly strong for people who had higher levels of negative emotion. This latter finding may help to explain why people with higher levels of negative emotion are more likely to engage in NSSI: they have more negative emotion to reduce, and thus more relief to gain. Using biological measures, Franklin and colleaguesobtained similar effects in both people with and without a history of NSSI. These new findings are especially interesting because it turns out that both general negative emotion and pain-induced negative emotion are processed in the same brain areas. This means that pain relief and emotional relief are essentially the same thing. Indeed, it was recently shown that pain relievers like acetaminophen also relieve emotional pain.

Many people find that it's hard to get emotional relief with traditional strategies (e.g., talking with friends). Consequently, they may resort to generating pain relief in order to generate emotional relief. Unfortunately, this also means that they have to generate acute, intense pain; that is, they have to engage in NSSI. Despite being an effective emotion relief strategy, NSSI is also a health-risk behavior that is associated with an increased risk of suicide. In short, NSSI can be a good thing for temporary emotional relief, but it's a bad thing for health.

The vast majority of people who engage in NSSI are not seeking to manipulate anyone and they're not wired differently than the rest of us. They simply tap into the natural emotional relief that accompanies the removal of intense, acute pain. They do this because they have trouble finding healthier ways to reduce their stress. Accordingly, ostracizing people who engage in NSSI only creates more stress and makes NSSI worse. The best way to help someone who engages in NSSI is to guide them to healthier ways to feel better.

http://www.scientificamerican.com/article.cfm?id=how-pain-can-make-you-fee&print=true

The Body Chronic

What gives me the right to have this blog? Well, I live with numerous chronic conditions and chronic pain on a daily basis. When I began being diagnosed with these things--and even before--there was no place on the internet that helped me adequately research everything. Instead, I was forced to piece information together myself.

Being a little older and a lot wiser, I decided that no person should go through what I went through to get the basic information and support necessary to navigate the waters surrounding chronic illness. I started this blog in the hopes of creating a support network for those who have a daily interaction with The Body Chronic.

http://bodychronic.blogspot.com/

International Association for the Study of Pain | Low-Resource Guide

Guide to Pain Management in Low-Resource Settings is intended to support health care providers in low-resource settings. Chapters were written by a multidisciplinary and multinational team of authors. Practitioners in settings with limited resources will benefit from easy-to-read information about simple and cost-effective approaches that can provide maximum effects in managing pain in their patients.

Topics range from the physiology and psychology of pain and principles of palliative care to management of patients with specific pain problems including various types of cancer, AIDS, sickle cell anemia, neuropathic pain, back pain, and visceral pain. Case reports provide illustrations of typical cases in the low-resource (often rural) setting in developing countries.

World-renowned experts provide chapters on setting up a pain management program, accessing resources for ensuring opioid availability, and setting up guidelines for local requirements. Authors with extensive clinical experience consider the integration of traditional medicines, modern pharmacotherapy (with consideration of the most cost-effective and readily available options), and techniques such as nerve blocks and radiation therapy.

http://www.iasp-pain.org/AM/Template.cfm?Section=Home&TEMPLATE=/CM/HTMLDisplay.cfm&CONTENTID=11669

The Headache That Wouldn’t Go Away - NYTimes.com

"My arm — something is biting my arm!" The 26-year-old woman struggled to sit up in bed. What's wrong? her husband asked, alarmed and suddenly wide awake. His wife didn't seem to hear him. Suddenly, her whole body began to jerk. Although he had never seen a seizure, the young man knew immediately that this was one. After a long and terrifying minute the jerking stopped and his wife lay quiet with her eyes closed, as if she were asleep. When he couldn't wake her, he picked up the phone and dialed 911.

In the emergency room, the young woman was sleepy and confused. She didn't remember the seizure. All she knew was that she felt bad earlier that day. Her shoulders ached and she had these strange shooting pains that ran up her neck, into her skull. She had a wicked headache too. Although she had this headache for months, it was much worse that day. At home she took a long hot bath and went to bed. She woke up in the ambulance.

She'd had no fever, she told the E.R. doctor, and hadn't felt sick — just sore. And now she felt fine. Her arm didn't hurt — in fact she couldn't remember that it had ever hurt. She still had the headache, though. She didn't smoke, didn't drink and took no medications. She moved to Boston from Bolivia several years earlier to get married and now had 15-month-old. Other than mild confusion, the patient's physical exam was normal. The E.R. doctor ordered blood tests to look for evidence of infection along with a CT scan of her head to look for a tumor.

Her headache started the year before, when she was pregnant. Before that she had the occasional headache, but back when her daughter was barely a bump, she got one that simply never went away. She told the midwife, who said it wasn't unusual to get headaches during pregnancy. But to the patient, this headache seemed different. It was like a vise on her head, just over her eyes. The pressure wasn't excruciating, just unrelenting. She took Tylenol, and that sometimes helped, but the headache always came back. Sometimes it even woke her up in the middle of the night. Finally the midwife sent her to her primary-care doctor.

Her doctor, a young internist in her first year of training (who asked that her name not be used), was worried about this headache. It had persisted for weeks and woke her patient up from sleep — that was unusual. The doctor recalled how happy the patient was when she called her with the news of her positive pregnancy test. And now barely showing at five months, she looked like the picture of expectant health. Had she had any weakness or numbness? Was there any loss of hearing or blurry vision? No, no and no. Well, she did have blurry vision, but that's only because she hated wearing her glasses.

The doctor focused her exam to look for any hint that this headache might be because of some kind of brain injury. She looked into the patient's eyes with the ophthalmoscope, scanning the retina for any signs of increased pressure inside the brain. She checked the patient's strength, coordination and reflexes. Nothing. Her exam was completely normal.

Headaches are common, accounting for some 18 million doctor visits a year. Most are completely benign, but up to 3 percent of patients with a headache severe enough to send them to the emergency room will have something worth worrying about. Doctors are taught to look for three types of potentially dangerous headaches: the first, the worst and the cursed. The first headache in someone who doesn't have headaches; the worst headache ever in someone who does; or a headache "cursed" by symptoms like weakness or numbness. A CT scan should be considered for these possibly life-threatening headaches. This headache fit into none of these informal categories.

This patient was woken up from sleep by her headaches — that's unusual, but the doctor knew that it was not one of the recommended reasons for getting a CT scan. And she was pregnant. A CT scan of the head requires a relatively high dose of radiation. Was the doctor's concern great enough to risk exposing the fetus based only on this somewhat unusual symptom? Not yet. Especially since there was another possible cause of the persistent headache — eyestrain. The patient was no longer wearing her glasses; she didn't even own a pair, she confessed. She should get new glasses, the doctor suggested, and see if wearing them helped her headache. If not, she should come back. Perhaps they would get a CT scan at that point.

It was more than a year later when the patient next came to see the doctor. She had gotten glasses, and though the headaches hadn't stopped, they seemed a bit better. It was no longer a constant pain. She had one maybe three to four times a week, and it lasted for a few hours and went away with a little ibuprofen. Besides, she was really too busy with the baby and her job to worry too much about them.

Then, six months after that last visit, she had this middle of the night seizure. In the E.R., the blood tests were all normal. Not so the CT scan. On the right side of the patient's brain, just over the eye, there was a bright circle of white, the size of a dime. Not a brain tumor. No, the radiologist said, this was a tiny worm, a larvae, the young offspring of a tapeworm. The parasite, known asTaenia solium, is transmitted through undercooked pork contaminated by tapeworm eggs. Once in the body, the eggs hatch and then attach themselves to the intestinal wall and within a few months can grow to up to 15 feet or more. A mature tapeworm will then release hundreds of eggs into the gut every day. If any of these are ingested, they can hatch, enter the bloodstream and, once there, can lodge almost anywhere in the body, although they usually end up in muscle and in the brain.

Although unusual in the United States, pork tapeworm is common in the developing world. And having these larvae in the brain, a condition known as neurocysticercosis, is the most common cause of adult epilepsy in South and Central America. The patient was probably infected with this tapeworm years earlier when she lived in Bolivia. This kind of infection can be asymptomatic for years. Once the doctors saw the CT scan, the patient was treated with an antiparasite medication for 30 days and started on antiseizure medications.

When her primary-care doctor heard that her patient had been diagnosed with neurocysticercosis, she scoured the patient's hospital chart and then her own notes. How had she missed that? What should she have done differently? She discussed the case with several of her teachers, who assured her that she had done everything properly. One of the frustrating truths in medicine is that it is possible to do everything right and still be wrong and miss the diagnosis.

The young doctor called the patient to see how she was doing and to schedule a follow-up visit. She was disappointed, though not completely surprised, when the patient chose to see a different doctor at the clinic.

In thinking about this case, the doctor's greatest regret is that she didn't get the chance to follow up on her patient and find out that her headaches didn't go away by just wearing glasses. When patients don't come back, the temptation is to assume they've gotten better. That is often not the case. Sometimes they've just given up. Now when she has a patient she is worried about, the doctor doesn't tell them to call her if they don't get better. Instead she has them make an appointment to come back in a couple of weeks. "If they are all better," the doctor told me, "they can cancel the appointment. But just in case they aren't — the way this woman wasn't — they can come back, and I can have another shot at the whole thing."

Lisa Sanders is the author of "Every Patient Tells a Story: Medical Mysteries and the Art of Diagnosis."

http://www.nytimes.com/2010/11/07/magazine/07FOB-Diagnosist-t.html?ref=magazine

StumbleUpon - Discover - Pain

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