Posts tagged pain
Posts tagged pain
TAU researchers study the long-term effects of torture on the human pain system
Israeli soldiers captured during the 1973 Yom Kippur War were subjected to brutal torture in Egypt and Syria. Held alone in tiny, filthy spaces for weeks or months, sometimes handcuffed and blindfolded, they suffered severe beatings, burns, electric shocks, starvation, and worse. And rather than receiving treatment, additional torture was inflicted on existing wounds.
Forty years later, research by Prof. Ruth Defrin of the Department of Physical Therapy in the Sackler Faculty of Medicine at Tel Aviv University shows that the ex-prisoners of war (POWs), continue to suffer from dysfunctional pain perception and regulation, likely as a result of their torture. The study — conducted in collaboration with Prof. Zahava Solomon and Prof. Karni Ginzburg of TAU’s Bob Shapell School of Social Work and Prof. Mario Mikulincer of the School of Psychology at the Interdisciplinary Center, Herzliya — was published in the European Journal of Pain.
"The human body’s pain system can either inhibit or excite pain. It’s two sides of the same coin," says Prof. Defrin. "Usually, when it does more of one, it does less of the other. But in Israeli ex-POWs, torture appears to have caused dysfunction in both directions. Our findings emphasize that tissue damage can have long-term systemic effects and needs to be treated immediately."
A painful legacy
The study focused on 104 combat veterans of the Yom Kippur War. Sixty of the men were taken prisoner during the war, and 44 of them were not. In the study, all were put through a battery of psychophysical pain tests — applying a heating device to one arm, submerging the other arm in a hot water bath, and pressing a nylon fiber into a middle finger. They also filled out psychological questionnaires.
The ex-POWs exhibited diminished pain inhibition (the degree to which the body eases one pain in response to another) and heightened pain excitation (the degree to which repeated exposure to the same sensation heightens the resulting pain). Based on these novel findings, the researchers conclude that the torture survivors’ bodies now regulate pain in a dysfunctional way.
It is not entirely clear whether the dysfunction is the result of years of chronic pain or of the original torture itself. But the ex-POWs exhibited worse pain regulation than the non-POW chronic pain sufferers in the study. And a statistical analysis of the test data also suggested that being tortured had a direct effect on their ability to regulate pain.
The researchers say non-physical torture may have also contributed to the ex-POWs’ chronic pain. Among other forms of oppression and humiliation, the ex-POWs were not allowed to use the toilet, cursed at and threatened, told demoralizing misinformation about their loved ones, and exposed to mock executions. In the later stages of captivity, most of the POWs were transferred to a group cell, where social isolation was replaced by intense friction, crowding, and loss of privacy.
"We think psychological torture also affects the physiological pain system," says Prof. Defrin. "We still have to fully analyze the data, but preliminary analysis suggests there is a connection."
Early life pain alters neural circuits in the brain that regulate stress, suggesting pain experienced by infants who often do not receive analgesics while undergoing tests and treatment in neonatal intensive care may permanently alter future responses to anxiety, stress and pain in adulthood, a research team led by Dr. Anne Murphy, associate director of the Neuroscience Institute at Georgia State University, has discovered.
An estimated 12 percent of live births in the U.S. are considered premature, researchers said. These infants often spend an average of 25 days in neonatal intensive care, where they endure 10-to-18 painful and inflammatory procedures each day, including insertion of feeding tubes and intravenous lines, intubation and repeated heel lance. Despite evidence that pain and stress circuitry in the brain are established and functional in preterm infants, about 65 percent of these procedures are performed without benefit of analgesia. Some clinical studies suggest early life pain has an immediate and long-term impact on responses to stress- and anxiety-provoking events.
The Georgia State study examined whether a single painful inflammatory procedure performed on male and female rat pups on the day of birth alters specific brain receptors that affect behavioral sensitivity to stress, anxiety and pain in adulthood. The findings demonstrated that such an experience is associated with site-specific changes in the brain that regulate how the pups responded to stressful situations. Alterations in how these receptors function have also been associated with mood disorders.
The study findings mirror what is now being reported clinically. Children who experienced unresolved pain following birth show reduced responsiveness to pain and stress.
“While a dampened response to painful and stressful situations may seem advantageous at first, the ability to respond appropriately to a potentially harmful stimulus is necessary in the long term,” Dr. Murphy said.
“The fact that less than 35 percent of infants undergoing painful and invasive procedures receive any sort of pre- or post-operative pain relief needs to be re-evaluated in order to reduce physical and mental health complications associated with preterm birth.”
Imagine significantly reducing a persistent migraine or fibromyalgia by a visit to a doctor who delivers low doses of electricity to the brain.
Alex DaSilva, assistant professor of prosthodontics at the University of Michigan, and colleagues are optimizing the next generation for such a technique, called high-definition transcranial direct current stimulation, or HD-tDCS.
The researchers have published several studies with the conventional tDCS, which also treats pain by “shocking” the brain with low doses of electrical current delivered noninvasively through electrodes placed on the scalp. The current modulates targeted areas of the brain, and one of the mechanisms is by activating the release of opioid-like painkillers.
HD-tDCS delivers an even more precisely focused current to the targeted areas of the brain. Preliminary reports have shown better pain relief in patients and a longer and more pronounced effect on the brain, said DaSilva, who heads the Headache and Orofacial Pain Effort Laboratory at the U-M School of Dentistry.
The increased precision of HD-tDCS means researchers can custom-place the electrodes to the skull. In this way, they can modulate specific areas in the brain to treat a wider range of conditions, such as neuropathic pain and stroke. Other uses include neurophysiological studies and cognitive and behavioral assessments.
One 20-minute session of HD-tDCS significantly reduced overall pain perception in fibromyalgia patients as described in one of the studies.
Researchers control the current by a portable device, which they hope physicians can eventually use in the clinic as a noninvasive treatment for chronic pain patients.
"We are working hard to make the technology available for clinical use at U-M," DaSilva said. "Our lab is getting a good number of emails from chronic pain patients looking for treatment."
The conventional technology is already available for many companies, and the HD-tDCS is being patented by the company of one of the developers.
To allow broad access and further investigation of the HD-tDCS technology by other researchers, DaSilva and colleagues released a scientific video demonstrating the step-by-step guideline of the research protocol: www.jove.com/embed/directions/50309?key=uahsva6y
Epigenetics, the study of changes in gene expression through mechanisms outside of the DNA structure, has been found to control a key pain receptor related to surgical incision pain, according to a study in the November issue of Anesthesiology. This study reveals new information about pain regulation in the spinal cord.
“Postoperative pain is an incompletely understood and only partially controllable condition that can result in suffering, medical complications, unplanned hospital admissions and disappointing surgery outcomes,” said David J. Clark, M.D., Ph.D., Professor of Anesthesia at Stanford University and Director of Pain Management at the VA Palo Alto Health Care System. “We know that histone acetylation and deacetylation modifies many cellular processes and produces distinct outcomes. In this study we found that histones can epigenetically activate or silence gene expression to either increase or decrease incision pain.”
Human DNA is wrapped around proteins called histones, much like thread is wrapped around a spool. When a histone undergoes deacetylation, the DNA wraps more tightly around the spool, effectively silencing genes. Conversely, when it undergoes acetylation, the DNA is loosened, allowing for transcription or modifications of genes to occur.
In this study, groups of mice had small surgical incisions made in their hind paws after being anesthetized. These mice were then regularly injected with suberoylanilide hydroxamic acid (SAHA), which prevents deacetylation (thus promoting gene transcription), or anacardic acid, which prevents acetylation (thus reducing gene transcription). The authors tested the animals daily for the degree of pain sensitivity in their hind paws.
The study found that regulation of histone acetylation can control pain sensitization after an incision. Specifically, maintaining histone in a relatively deacetylated state reduced hypersensitivity after incision. This is due, in part, to the epigenetic regulation of a specific gene known as CXCR2 and one of its chemokine ligands (KC). The authors also found that these epigenetic changes far outlasted the recovery of animals from their incisions, a property that might help explain why some patients suffer from chronic postoperative pain. Study authors suggest that looking into the roles of these epigenetic mechanisms may help scientists find new ways to treat or prevent acute and chronic postoperative pain in the future.
“Epigenetics is a relatively underappreciated area of science, but the discoveries yet to be made in this field will be many,” said Dr. Clark. “While fascinating information has been found by studying specific genes, we need to bridge the gap in science and focus on groups or systems of many genes simultaneously, which could be give us clues to greater breakthroughs in pain control and other areas of medicine.”
The painful, potentially deadly stings of bark scorpions are nothing more than a slight nuisance to grasshopper mice, which voraciously kill and consume their prey with ease. When stung, the mice briefly lick their paws and move in again for the kill.
The grasshopper mice are essentially numb to the pain, scientists have found, because the scorpion toxin acts as an analgesic rather than a pain stimulant.
The scientists published their research this week in Science.
Ashlee Rowe, lead author of the paper, previously discovered that grasshopper mice, which are native to the southwestern United States, are generally resistant to the bark scorpion toxin, which can kill other animals.
It is still unknown why the toxin is not lethal to the mice.
“This venom kills other mammals of similar size,” said Rowe, Michigan State University assistant professor of neuroscience and zoology. “The grasshopper mouse has developed the evolutionary equivalent of martial arts to use the scorpions’ greatest strength against them.”
Rowe, who conducted the research while at The University of Texas at Austin, and her colleagues ventured into the desert and collected scorpions and mice for their experiments.
To test whether the grasshopper mice felt pain from the toxin, the scientists injected small amounts of scorpion venom or nontoxic saline solution in the mice’s paws. Surprisingly, the mice licked their paws (a typical toxin response) much less when injected with the scorpion toxin than when injected with a nontoxic saline solution.
“This seemed completely ridiculous,” said Harold Zakon, professor of neuroscience at The University of Texas at Austin. “One would think that the venom would at least cause a little more pain than the saline solution. This would mean that perhaps the toxin plays a role as an analgesic. This seemed very far out, but we wanted to test it anyway.”
Rowe and Zakon discovered that the bark scorpion toxin acts as an analgesic by binding to sodium channels in the mouse pain neurons, and this blocks the neuron from firing a pain signal to the brain.
Pain neurons have a couple of different sodium channels, called 1.7 and 1.8, and research has shown that when toxins bind to 1.7 channels, the channels open, sodium flows in and the pain neuron fires.
By sequencing the genes for both the 1.7 and 1.8 sodium channels, the scientists discovered that channel 1.8 in the grasshopper mice has amino acids different from mammals that are sensitive to bark scorpion stings, such as house mice, rats and humans. They then found that the scorpion toxin binds to one of these amino acids to block the activation of channel 1.8 and thus inhibit the pain response.
“Incredibly, there is one amino acid substitution that can totally alter the behavior of the toxin and block the channel,” said Zakon.
The riddle hasn’t been completely solved just yet, though, Rowe said.
“We know the region of the channel where this is taking place and the amino acids involved,” she said. “But there’s something else that’s playing a role, and that’s what I’m focusing on next.”
Some resistance to prey toxins in mammals has been found in other species. The mongoose, for example, is resistant to the cobra. And naked mole rats’ eyes do not burn in pain when carbon dioxide builds up in their underground tunnels.
This study, however, is the first to find that an amino acid substitution in sodium channel 1.8 can have an analgesic effect.
Rowe said studies such as this could someday help researchers target these sodium channels for the development of analgesic medications for humans.
Anyone who has suffered through sleepless nights due to uncontrollable itching knows that not all itching is the same. New research at Washington University School of Medicine in St. Louis explains why.
Working in mice, the scientists have shown that chronic itching, which can occur in many medical conditions, from eczema and psoriasis to kidney failure and liver disease, is different from the fleeting urge to scratch a mosquito bite.
That’s because chronic itching appears to incorporate more than just the nerve cells, or neurons, that normally transmit itch signals. The researchers found that in chronic itching, neurons that send itch signals also co-opt pain neurons to intensify the itch sensation.
The new discovery may lead to more effective treatments for chronic itching that target activity in neurons involved in both pain and itch. The research is reported online Oct. 15 in The Journal of Clinical Investigation and will appear in the November print issue.
“In normal itching, there’s a fixed pathway that transmits the itch signal,” said senior investigator Zhou-Feng Chen, PhD, who directs Washington University’s Center for the Study of Itch. “But with chronic itching, many neurons can be turned into itch neurons, including those that typically transmit pain signals. That helps explain why chronic itching can be so excruciating.”
Chen, a professor of anesthesiology, and his colleagues generated mice in which a protein called BRAF always is active and continually sends signals inside itch neurons. The BRAF gene and the protein it makes are involved in the body’s pain response, but scientists didn’t know whether the gene also played a role in itch.
“We thought the animals might be prone to feeling pain rather than itching,” Chen explained. “To our great surprise, the mice scratched spontaneously. At first, we didn’t know why they were scratching, but it turns out we developed a mouse model of chronic itch.”
Further studies discovered that the BRAF protein could turn on many itch genes, and they showed similar changes of gene expression in mice with chronic itch induced by dry skin and in mice with allergic contact dermatitis, two of the skin conditions that frequently cause people to scratch incessantly.
The findings suggest that targeting proteins in the BRAF pathway may open new avenues for treating chronic itch, a condition in which few therapies are effective. One possibility includes using drugs that are prescribed to treat pain.
“Certain drugs are used to inhibit some of the same targets in patients with chronic pain, and those medications also may quiet down itch,” Chen said.
In earlier studies, Chen identified gastrin-releasing peptide (GRP), a substance that carries itch signals to a gene called GRPR (gastrin-releasing peptide receptor) in the spinal cord. In the new study, GRP and GRPR activity was doubled in the genetically altered mice, which could account for some of the increase in the intensity of itching. But other genes that normally are activated by pain also were turned on in the itch pathway, further intensifying the itch sensation.
Surprisingly, however, the mice had a normal response to pain, indicating that the pain and itch pathways are very different.
Unlike scratching a mosquito bite, which usually is only a temporary sensation, chronic itch can persist much longer, according to Chen, also a professor of psychiatry and of developmental biology. His team found that the mice in this study not only scratched spontaneously but also had more severe responses when exposed to substances that normally would induce acute itching.
“In people, chronic itching can last for weeks, months or even years,” Chen said. “These mice are helping us to understand the pathways that can be involved in transmitting itch signals and the many contributors to chronic itching. There are many pathways leading from BRAF, and all of these could be potential targets for anti-itch therapies.”
Finding that the opioid system can act to ease social pain, not just physical pain, may aid understanding of depression and social anxiety
A brain image showing in orange/red one area of the brain where the natural painkiller (opioid) system was highly active in research volunteers who are experiencing social rejection. This region, called the amygdala, was one of several where the U-M team recorded the first images of this system responding to social pain, not just physical pain. Studying this response, and the variation between people, could aid understanding of depression and anxiety. Credited to UofM Health.
“Sticks and stones may break my bones, but words will never hurt me,” goes the playground rhyme that’s supposed to help children endure taunts from classmates. But a new study suggests that there’s more going on inside our brains when someone snubs us – and that the brain may have its own way of easing social pain.
The findings, recently published in Molecular Psychiatry by a University of Michigan Medical School team, show that the brain’s natural painkiller system responds to social rejection – not just physical injury.
What’s more, people who score high on a personality trait called resilience – the ability to adjust to environmental change – had the highest amount of natural painkiller activation.
A girl who does not feel physical pain has helped researchers identify a gene mutation that disrupts pain perception. The discovery may spur the development of new painkillers that will block pain signals in the same way.
People with congenital analgesia cannot feel physical pain and often injure themselves as a result – they might badly scald their skin, for example, through being unaware that they are touching something hot.
By comparing the gene sequence of a girl with the disorder against those of her parents, who do not, Ingo Kurth at Jena University Hospital in Germany and his colleagues identified a mutation in a gene called SCN11A.
This gene controls the development of channels on pain-sensing neurons. Sodium ions travel through these channels, creating electrical nerve impulses that are sent to the brain, which registers pain.
Overactivity in the mutated version of SCN11A prevents the build-up of the charge that the neurons need to transmit an electrical impulse, numbing the body to pain. “The outcome is blocked transmission of pain signals,” says Kurth.
To confirm their findings, the team inserted a mutated version of SCN11A into mice and tested their ability to perceive pain. They found that 11 per cent of the mice with the modified gene developed injuries similar to those seen in people with congenital analgesia, such as bone fractures and skin wounds. They also tested a control group of mice with the normal SCN11A gene, none of which developed such injuries.
The altered mice also took 2.5 times longer on average than the control group to react to the “tail flick” pain test, which measures how long it takes for mice to flick their tails when exposed to a hot light beam. “What became clear from our experiments is that although there are similarities between mice and men with the mutation, the degree of pain insensitivity is more prominent in humans,” says Kurth.
The team has now begun the search for drugs that block the SCN11A channel. “It would require drugs that selectively block this but not other sodium channels, which is far from simple,” says Kurth.
"This is a cracking paper, and great science," says Geoffrey Woods of the University of Cambridge, whose team discovered in 2006 that mutations in another, closely related ion channel gene can cause insensitivity to pain. "It’s completely unexpected and not what people had been looking for," he says.
Woods says that there are three ion channels, called SCN9A, 10A and 11A, on pain-sensing neurons. People experience no pain when either of the first two don’t work, and agonising pain when they’re overactive. “With this new gene, it’s the opposite: when it’s overactive, they feel no pain. So maybe it’s some kind of gatekeeper that stops neurons from firing too often, but cancels pain signals completely when it’s overactive,” he says. “If you could get a drug that made SCN11A overactive, it should be a fantastic analgesic.”
"It’s fascinating that SCN11A appears to work the other way, and that could really advance our knowledge of the role of sodium channels in pain perception, which is a very hot topic,” says Jeffrey Mogil at McGill University in Canada, who was not involved in the new study.
Bad language could be good for you, a new study shows. For the first time, psychologists have found that swearing may serve an important function in relieving pain.
The study, published in the journal NeuroReport, measured how long college students could keep their hands immersed in cold water. During the chilly exercise, they could repeat an expletive of their choice or chant a neutral word. When swearing, the 67 student volunteers reported less pain and on average endured about 40 seconds longer.
Although cursing is notoriously decried in the public debate, researchers are now beginning to question the idea that the phenomenon is all bad. “Swearing is such a common response to pain that there has to be an underlying reason why we do it,” says psychologist Richard Stephens of Keele University in England, who led the study. And indeed, the findings point to one possible benefit: “I would advise people, if they hurt themselves, to swear,” he adds.
How swearing achieves its physical effects is unclear, but the researchers speculate that brain circuitry linked to emotion is involved. Earlier studies have shown that unlike normal language, which relies on the outer few millimeters in the left hemisphere of the brain, expletives hinge on evolutionarily ancient structures buried deep inside the right half.
One such structure is the amygdala, an almond-shaped group of neurons that can trigger a fight-or-flight response in which our heart rate climbs and we become less sensitive to pain. Indeed, the students’ heart rates rose when they swore, a fact the researchers say suggests that the amygdala was activated.
That explanation is backed by other experts in the field. Psychologist Steven Pinker of Harvard University, whose book The Stuff of Thought (Viking Adult, 2007) includes a detailed analysis of swearing, compared the situation with what happens in the brain of a cat that somebody accidentally sits on. “I suspect that swearing taps into a defensive reflex in which an animal that is suddenly injured or confined erupts in a furious struggle, accompanied by an angry vocalization, to startle and intimidate an attacker,” he says.
But cursing is more than just aggression, explains Timothy Jay, a psychologist at the Massachusetts College of Liberal Arts who has studied our use of profanities for the past 35 years. “It allows us to vent or express anger, joy, surprise, happiness,” he remarks. “It’s like the horn on your car, you can do a lot of things with that, it’s built into you.”
In extreme cases, the hotline to the brain’s emotional system can make swearing harmful, as when road rage escalates into physical violence. But when the hammer slips, some well-chosen swearwords might help dull the pain.
There is a catch, though: The more we swear, the less emotionally potent the words become, Stephens cautions. And without emotion, all that is left of a swearword is the word itself, unlikely to soothe anyone’s pain.
Fish do not feel pain the way humans do. That is the conclusion drawn by an international team of researchers consisting of neurobiologists, behavioural ecologists and fishery scientists. One contributor to the landmark study was Prof. Dr. Robert Arlinghaus of the Leibniz Institute of Freshwater Ecology and Inland Fisheries and of the Humboldt University in Berlin.
On July 13th a revised animal protection act has come into effect in Germany. But anyone who expects it to contain concrete statements regarding the handling of fish will be disappointed. The legislator seemingly had already found its answer to the fish issue. Accordingly, fish are sentient vertebrates who must be protected against cruel acts performed by humans against animals. Anyone in Germany who, without due cause, kills vertebrates or inflicts severe pain or suffering on them has to face penal consequences as well as severe fines or even prison sentences. Now, the question of whether or not fish are really able to feel pain or suffer in human terms is once again on the agenda. A final decision would have far-reaching consequences for millions of anglers, fishers, aquarists, fish farmers and fish scientists. To this end, a research team consisting of seven people has examined all significant studies on the subject of fish pain. During their research the scientists from Europe, Canada, Australia and the USA have discovered many deficiencies. These are the authors’ main points of criticism: Fish do not have the neuro-physiological capacity for a conscious awareness of pain. In addition, behavioural reactions by fish to seemingly painful impulses were evaluated according to human criteria and were thus misinterpreted. There is still no final proof that fish can feel pain.
This is how it works for humans
To be able to understand the researchers’ criticism you first have to comprehend how pain perception works for humans. Injuries stimulate what is known as nociceptors. These receptors send electrical signals through nerve-lines and the spinal cord to the cerebral cortex (neocortex). With full awareness, this is where they are processed into a sensation of pain. However, even severe injuries do not necessarily have to result in an experience of pain. As an emotional state, pain can for example be intensified through engendering fear and it can also be mentally constructed without any tissue damage. Conversely, any stimulation of the nociceptors can be unconsciously processed without the organism having an experience of pain. This principle is used in cases such as anaesthesia. It is for this reason that pain research distinguishes between a conscious awareness of pain and an unconscious processing of impulses through nociception, the latter of which can also lead to complex hormonal reactions, behavioural responses as well as to learning avoidance reactions. Therefore, nociceptive reactions can never be equated with pain, and are thus, strictly speaking, no prerequisite for pain.
Fish are not comparable to humans in terms of anatomy and physiology
Unlike humans fish do not possess a neocortex, which is the first indicator of doubt regarding the pain awareness of fish. Furthermore, certain nerve fibres in mammals (known as c-nociceptors) have been shown to be involved in the sensation of intense experiences of pain. All primitive cartilaginous fish subject to the study, such as sharks and rays, show a complete lack of these fibres and all bony fish – which includes all common types of fish such as carp and trout – very rarely have them. In this respect, the physiological prerequisites for a conscious experience of pain are hardly developed in fish. However, bony fish certainly possess simple nociceptors and they do of course show reactions to injuries and other interventions. But it is not known whether this is perceived as pain.
There is often a lack of distinction between conscious pain and unconscious nociception
The current overview-study raises the complaint that a great majority of all published studies evaluate a fish’s reaction to a seemingly painful impulse - such as rubbing the injured body part against an object or the discontinuation of the feed intake - as an indication of pain. However, this methodology does not prove verifiably whether the reaction was due to a conscious sensation of pain or an unconscious impulse perception by means of nociception, or a combination of the two. Basically, it is very difficult to deduct underlying emotional states based on behavioural responses. Moreover, fish often show only minor or no reactions at all to interventions which would be extremely painful to us and to other mammals. Pain killers such as morphine that are effective for humans were either ineffective in fish or were only effective in astronomically high doses that, for small mammals, would have meant immediate death from shock. These findings suggest that fish either have absolutely no awareness of pain in human terms or they react completely different to pain. By and large, it is absolutely not advisable to interpret the behaviour of fish from a human perspective.
What does all this mean for those who use fish?
In legal terms it is forbidden to inflict pain, suffering or harm on animals without due cause according to §1 of the German Animal Protection Act. However, the criteria for when such acts are punishable is exclusive tied to the animal’s ability to feel pain and suffering in accordance with §17 of the very same Act. The new study severely doubts that fish are aware of pain as defined by human terms. Therefore, it should actually no longer constitute a criminal offence if, for example, an angler releases a harvestable fish at his own discretion instead of eating it. However, at a legal and moral level, the recently published doubts regarding the awareness of pain in fish do not release anybody from their responsibility of having to justify all uses of fishes in a socially acceptable way and to minimise any form of stress and damage to the fish when interacting with it.
Rose, J.D., Arlinghaus, R., Cooke, S.J., Diggles, B.K., Sawynok, W., Stevens, E.D. & Wynne, C.D.L (in print) Can fish really feel pain? Fish and Fisheries