Neanderthal gene variants associated with greater pain sensitivity

People who carry three gene variants that have bene inherited from Neanderthals are more sensitive to some types of pain, according to a new study co-led by UCL researchers.

The findings, published in Communications Biology, are the latest findings to show how past interbreeding with Neanderthals has influenced the genetics of modern humans.

The researchers found that people carrying three so-called Neanderthal variants in the gene SCN9A, which is implicated in sensory neurons, are more sensitive to pain from skin pricking after prior exposure to mustard oil.

Previous research has identified three variations in the SCN9A gene -- known as M932L, V991L, and D1908G -- in sequenced Neanderthal genomes and reports of greater pain sensitivity among humans carrying all three variants. However, prior to this study the specific sensory responses affected by these variants was unclear.

An international team led by researchers at UCL, Aix-Marseille University, University of Toulouse, Open University, Fudan University, and Oxford University, and part-funded by Wellcome, measured the pain thresholds of 1,963 people from Colombia in response to a range of stimuli.

The SCN9A gene encodes a sodium channel that is expressed at high levels in sensory neurons that detect signals from damaged tissue. The researchers found that the D1908G variant of the gene was present in around 20% of chromosomes within this population and around 30% of chromosomes carrying this variant also carried the M932L and V991L variants.

The authors found that the three variants were associated with a lower pain threshold in response to skin pricking after prior exposure to mustard oil, but not in response to heat or pressure. Additionally, carrying all three variants was associated with greater pain sensitivity than carrying only one.

When they analysed the genomic region including SCN9A using genetic data from 5,971 people from Brazil, Chile, Colombia, Mexico and Peru, the authors found that the three Neanderthal variants were more common in populations with higher proportions of Native American ancestry, such as the Peruvian population, in which the average proportion of Native American ancestry was 66%.

The authors propose that the Neanderthal variants may sensitise sensory neurons by altering the threshold at which a nerve impulse is generated. They speculate that the variants may be more common in populations with higher proportions of Native American ancestry as a result of random chance and population bottlenecks that occurred during the initial occupation of the Americas. Although acute pain can moderate behaviour and prevent further injury, the scientists that say additional research is needed to determine whether carrying these variants and having greater pain sensitivity may have been advantageous during human evolution.

Previous research by co-corresponding author Dr Kaustubh Adhikari (UCL Genetics, Evolution & Environment and The Open University) has shown that humans also inherited some genetic material from Neanderthals affecting the shape of our noses.*

Dr Adhikari commented: "In the last 15 years, since the Neanderthal genome was first sequenced, we have been learning more and more about what we have inherited from them as a result of interbreeding tens of thousands of years ago.

"Pain sensitivity is an important survival trait that enables us to avoid painful things that could cause us serious harm. Our findings suggest that Neanderthals may have been more sensitive to certain types of pain, but further research is needed for us to understand why that is the case, and whether these specific genetic variants were evolutionarily advantageous."

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How alcohol consumption contributes to chronic pain

Chronic alcohol consumption may make people more sensitive to pain through two different molecular mechanisms -- one driven by alcohol intake and one by alcohol withdrawal. That is one new conclusion by scientists at Scripps Research on the complex links between alcohol and pain.

The research, published in the British Journal of Pharmacology on April 12, 2023, also suggests potential new drug targets for treating alcohol-associated chronic pain and hypersensitivity.

"There is an urgent need to better understand the two-way street between chronic pain and alcohol dependence," says senior author Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine, and a professor of neuroscience at Scripps Research. "Pain is both a widespread symptom in patients suffering from alcohol dependence, as well as a reason why people are driven to drink again."

Alcohol use disorder (AUD), which encompasses the conditions commonly called alcohol abuse, alcohol dependence and alcohol addiction, affects 29.5 million people in the U.S. according to the 2021 National Survey on Drug Use and Health. Over time, AUD can trigger the development of numerous chronic diseases, including heart disease, stroke, liver disease and some cancers.

Among the many impacts of long-term alcohol consumption is pain: more than half of people with AUD experience persistent pain of some type. This includes alcoholic neuropathy, which is nerve damage that causes chronic pain and other symptoms. Studies have also found that AUD is associated with changes in how the brain processes pain signals, as well as changes to how immune system activation occurs. In turn, this pain can lead to increased alcohol consumption. Moreover, during withdrawal, people with AUD can experience allodynia, in which a harmless stimulus is perceived as painful.

Roberto and her colleagues were interested in learning the underlying causes of these different types of alcohol-related pain. In the new study, they compared three groups of adult mice: animals that were dependent on alcohol (excessive drinkers), animals that had limited access to alcohol and were not considered dependent (moderate drinkers), and those that had never been given alcohol.

In dependent mice, allodynia developed during alcohol withdrawal, and subsequent alcohol access significantly decreased pain sensitivity. Separately, about half of the mice that were not dependent on alcohol also showed signs of increased pain sensitivity during alcohol withdrawal but, unlike the dependent mice, this neuropathy was not reversed by re-exposure to alcohol.

When Roberto's group then measured levels of inflammatory proteins in the animals, they discovered that while inflammation pathways were elevated in both dependent and non-dependent animals, specific molecules were only increased in dependent mice. This indicates that different molecular mechanisms may drive the two types of pain. It also suggests which inflammatory proteins may be useful as drug targets to combat alcohol-related pain.

"These two types of pain vary greatly, which is why it is important to be able to distinguish between them and develop different ways to treat each type," says first author Vittoria Borgonetti, PhD, a postdoctoral associate at Scripps Research.

Roberto's group is continuing studies on how these molecules might be used to diagnose or treat alcohol-related chronic pain conditions.

"Our goal is to unveil new potential molecular targets that can be used to distinguish these types of pain and potentially be used in the future for the development of therapies," says co-senior author Nicoletta Galeotti, PhD, associate professor of preclinical pharmacology at the University of Florence.

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Turn up your favorite song to improve medication efficacy

While listening to a favorite song is a known mood booster, researchers at Michigan State University have discovered that music-listening interventions also can make medicines more effective.

"Music-listening interventions are like over-the-counter medications," said Jason Kiernan, an assistant professor in the College of Nursing. "You don't need a doctor to prescribe them."

While previous research studies have used music-listening interventions as a tool to treat pain and anxiety, Kiernan took a novel approach by studying the effects of music-listening interventions on chemotherapy-induced nausea.

"Pain and anxiety are both neurological phenomena and are interpreted in the brain as a state," Kiernan said. "Chemotherapy-induced nausea is not a stomach condition; it is a neurological one."

The small pilot study included 12 patients undergoing chemotherapy treatment who agreed to listen to their favorite music for 30 minutes each time they needed to take their as-needed anti-nausea medication. They repeated the music intervention anytime nausea occurred over the five days beyond their chemotherapy treatment. The patients in the study provided a total of 64 events.

"When we listen to music, our brains fire all kinds of neurons," Kiernan said.

While Kiernan did see a reduction in the ratings of patients' nausea severity and their distress (how much it bothered them to be nauseous), he cautions that it is difficult to isolate whether it was the gradual release of the medication doing its job or the increased benefit of the music. For future studies, Kiernan is drawing inspiration from another previously published study that measured the amount of serotonin, a neurotransmitter, that was released by platelets in the blood after listening to unpleasant and pleasant music.

"Serotonin is the major neurotransmitter that causes chemotherapy-induced nausea," Kiernan said. "Cancer patients take medications to block serotonin's effects."

During that previous study, researchers found that patients who listened to pleasant music experienced the lowest levels of serotonin release, indicating that the serotonin stayed in the blood platelets and was not released to circulate throughout the body. Results also showed that after listening to music they found unpleasant, patients experienced greater stress and increased levels of serotonin release.

"This was intriguing because it provides a neurochemical explanation and a possible way to measure serotonin and the blood platelet release of serotonin in my study," Kiernan said. "In 10 to 20 years, wouldn't it be neat if you could use a nonpharmacological intervention like listening to 10 minutes of your favorite music to complement a medicine?"

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Preterm babies do not habituate to repeated pain

Preterm infants do not get used to repeated pain in the way that full-term infants, children and adults do habituate to pain, finds a study led by UCL (University College London) researchers.

The authors of the new Current Biology paper say that if preterm infants have not yet developed the mechanism that enables people to get used to moderate pain, medical procedures in their first few weeks of life could potentially impact their development.

Lead author Dr Lorenzo Fabrizi (UCL Neuroscience, Physiology & Pharmacology) said: "The way that we can get used to things can be seen as the simplest example of behavioural and brain plasticity, and it is a basic part of memory and learning. Pain habituation is important because it enables us to preserve physical, emotional, and cognitive resources by not overreacting to pain that is unavoidable or not life-threatening.

"Our findings suggest that the ability to get used to repeated pain might develop during the third trimester of pregnancy, so that babies born prematurely have not yet developed this ability that full-term babies have right from birth."

The study involved 20 infants at University College London Hospitals (UCLH). Half of them were preterm (and tested while still younger than 35 weeks gestational age*), while the other half were either born at full term (seven infants) or preterm but tested at term age (three infants). The two groups were comparable in terms of their actual postnatal age, as the preterm babies had a median age of 14 days, compared to 10 days among the full-term (or term age) group.

The researchers were measuring the infants' responses to a painful but clinically required heel lance (blood test), which was conducted twice (three to 18 minutes apart) for each infant (two lances are sometimes required to collect enough blood; this is not needed for most infants so only those that needed a second lance were included in the study).

Heel lances can elicit substantial pain responses in infants, but it was not previously known whether this decreases on repeated lances. To understand this, the researchers recorded the infants' brain activity with EEG (electroencephalography) electrodes placed on the scalp, and their heart rates using ECG (electrocardiography), while also monitoring their facial expressions and reflexes in withdrawing the leg.

The researchers found that the brain activity was not as strong immediately after the second heel lance, compared to the first, suggesting a habituation response, but this was only the case for full-term infants. They found a similar pattern for heart rate and facial expressions, as preterm infants reacted just as strongly to both heel lances, while the full-term infants appeared to habituate to the pain.

The team says this habituation response might be due to the full-term infants anticipating the imminent pain when they receive a second heel lance, so their reaction is less pronounced, or it may instead or additionally be due to their brains modulating their reflexive survival responses.

They add that habituation to pain might protect the full-term infants, but not those who were pre-term, from potential consequences to their development.

First author Dr Mohammed Rupawala (UCL Neuroscience, Physiology & Pharmacology) said: "While unpleasant and painful clinical procedures are necessary for many young infants, there is the potential to impact their development, such as by altered pain perception, or potentially reduced grey matter or disrupted white matter in the brain."

Co-author Dr Judith Meek, consultant neonatologist at UCLH, said: "This work raises awareness of the extra vulnerability of premature babies to pain. Clinicians need to do their best to protect them from repeated painful experiences. This should be regarded as an essential component of brain oriented newborn care."

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Perceived choice in music listening is linked to pain relief

A new study explores the use of music-listening to relieve acute pain, finding that people who were given the impression that they had control over the music they heard experienced more pain relief than people who were not given such control. Dr. Claire Howlin of Queen Mary University of London, U.K., and colleagues from University College Dublin, Ireland, present these findings in the open-access journal PLOS ONE on August 3, 2022.

Music listening can be used for pain relief, especially for chronic pain, i.e., pain lasting more than 12 weeks. However, the underlying mechanisms of these benefits are unclear, especially for acute pain, i.e., pain lasting less than 12 weeks. Basic musical features, such as tempo or energy, seem to be less important for pain relief; instead, feeling able to make decisions about the music may be key for pain relief. However, previous work has largely focused on findings from lab-based samples that did not explore real-world, pre-existing acute pain.

To improve understanding, Howlin and colleagues asked 286 adults experiencing real-world acute pain to rate their pain before and after listening to a music track. The track was specially composed in two different versions of varying complexity. Participants were randomly assigned to hear either the low- or high-complexity version, and some were randomly selected to be given the impression that they had some control over the musical qualities of the track, although they heard the same track regardless of their choice.

The researchers found that participants who felt they had control over the music experienced greater relief in the intensity of their pain than participants who were not given such an impression. In questionnaires, participants reported enjoying both versions of the track, but no links were found between music complexity and amount of pain relief. Additionally, participants who engage more actively with music in their everyday life experienced even greater pain-relief benefits from having a sense of control over the track used in this study.

These findings suggest that choice and engagement with music are important for optimizing its pain-relief potential. Future research could further explore the relationship between music choice and subsequent engagement, as well as strategies for boosting engagement to improve pain relief.

The authors add: "Now we know that the act of choosing music is an important part of the wellbeing benefits that we see from music listening. It's likely that people listen more closely, or more carefully when they choose the music themselves."

From Science Daily

How sound reduces pain in mice

An international team of scientists has identified the neural mechanisms through which sound blunts pain in mice. The findings, which could inform development of safer methods to treat pain, were published in Science. The study was led by researchers at the National Institute of Dental and Craniofacial Research (NIDCR); the University of Science and Technology of China, Hefei; and Anhui Medical University, Hefei, China. NIDCR is part of the National Institutes of Health.

"We need more effective methods of managing acute and chronic pain, and that starts with gaining a better understanding of the basic neural processes that regulate pain," said NIDCR Director Rena D'Souza, D.D.S., Ph.D. "By uncovering the circuitry that mediates the pain-reducing effects of sound in mice, this study adds critical knowledge that could ultimately inform new approaches for pain therapy."

Dating back to 1960, studies in humans have shown that music and other kinds of sound can help alleviate acute and chronic pain, including pain from dental and medical surgery, labor and delivery, and cancer. However, how the brain produces this pain reduction, or analgesia, was less clear.

"Human brain imaging studies have implicated certain areas of the brain in music-induced analgesia, but these are only associations," said co-senior author Yuanyuan (Kevin) Liu, Ph.D., a Stadtman tenure-track investigator at NIDCR. "In animals, we can more fully explore and manipulate the circuitry to identify the neural substrates involved."

The researchers first exposed mice with inflamed paws to three types of sound: a pleasant piece of classical music, an unpleasant rearrangement of the same piece, and white noise. Surprisingly, all three types of sound, when played at a low intensity relative to background noise (about the level of a whisper) reduced pain sensitivity in the mice. Higher intensities of the same sounds had no effect on animals' pain responses.

"We were really surprised that the intensity of sound, and not the category or perceived pleasantness of sound would matter," Liu said.

To explore the brain circuitry underlying this effect, the researchers used non-infectious viruses coupled with fluorescent proteins to trace connections between brain regions. They identified a route from the auditory cortex, which receives and processes information about sound, to the thalamus, which acts as a relay station for sensory signals, including pain, from the body. In freely moving mice, low-intensity white noise reduced the activity of neurons at the receiving end of the pathway in the thalamus.

In the absence of sound, suppressing the pathway with light- and small molecule-based techniques mimicked the pain-blunting effects of low-intensity noise, while turning on the pathway restored animals' sensitivity to pain.

Liu said it is unclear if similar brain processes are involved in humans, or whether other aspects of sound, such as its perceived harmony or pleasantness, are important for human pain relief.

"We don't know if human music means anything to rodents, but it has many different meanings to humans -- you have a lot of emotional components," he said.

The results could give scientists a starting point for studies to determine whether the animal findings apply to humans, and ultimately could inform development of safer alternatives to opioids for treating pain.

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New research may explain unexpected effects of common painkillers

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin are widely used to treat pain and inflammation. But even at similar doses, different NSAIDs can have unexpected and unexplained effects on many diseases, including heart disease and cancer.

Now, a new Yale-led study has uncovered a previously unknown process by which some NSAIDs affect the body. The finding may explain why similar NSAIDs produce a range of clinical outcomes and could inform how the drugs are used in the future.

The study was published May 23 in the journal Immunity.

Until now, the anti-inflammatory effects of NSAIDs were believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs. For example, some NSAIDs prevent heart disease while others cause it, some NSAIDs have been linked to decreased incidence of colorectal cancer, and various NSAIDs can have a wide range of effects on asthma.

Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects.

The research showed that only some NSAIDs -- including indomethacin, which is used to treat arthritis and gout, and ibuprofen -- also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many actions, triggers anti-inflammatory processes in the body.

"It's interesting and exciting that NSAIDs have a different mode of action than what was known previously," said Anna Eisenstein, an instructor at the Yale School of Medicine and lead author of the study. "And because people use NSAIDs so frequently, it's important we know what they're doing in the body."

The research team can't say for sure that NSAIDs' unexpected effects are due to NRF2 -- that will require more research. "But I think these findings are suggestive of that," Eisenstein said.

Eisenstein is now looking into some of the drugs' dermatological effects -- causing rashes, exacerbating hives, and worsening allergies -- and whether they are mediated by NRF2.

This discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have impacts on how inflammation is treated and how NSAIDs are used.

For instance, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer's disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs. Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they're most likely to treat.

The findings may also point to entirely new applications for NSAIDs, said Eisenstein.

NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation. And the protein has been implicated in aging, longevity, and cellular stress reduction.

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Taste, temperature and pain sensations are neurologically linked

If you have eaten a chili pepper, you have likely felt how your body reacts to the spicy hot sensation. New research published by biologists at the University of Oklahoma shows that the brain categorizes taste, temperature and pain-related sensations in a common region of the brain. The researchers suggest the brain also groups these sensations together as either pleasant or aversive, potentially offering new insights into how scientists might better understand the body's response to and treatment of pain.

"The spicy hot sensation you get from a chili pepper is actually a pain sensation…this follows activation of pain-related fibers that innervate the tongue and are heat sensitive," said Christian H. Lemon, Ph.D., an associate professor in the Department of Biology in the Dodge Family College of Arts and Sciences at OU. "What happens is a chemical in chili peppers, called capsaicin, causes activation of pain fibers and 'tricks' the neurons to react like there is a heat stimulus in your mouth, so you'll notice when you eat spicy foods, your body will react to try to remove the heat - your blood vessels can dilate and you can start to sweat because your body 'thinks' it's overheating."

Lemon, who is also a member of the OU Institute for Biomedical Engineering, Science and Technology, and researchers in his lab, Jinrong Li, Ph.D., and?Md Sams Sazzad Ali, Ph.D., published an article in The Journal of Neuroscience that examines how taste, temperature and pain-related sensations interact in the brain. Their article was also selected for the journal's Featured Research section.

"Neural messages associated with pain are partly carried by neural circuits involved with sensing temperature," Lemon said. "This would explain, for example, why when you touch a hot stove, it's a burning pain. There are intimate ties between temperature and pain, and there are intimate ties between temperature and taste…just about everything we eat is either warmed or cooled, and that's known to have a fairly robust effect on the way we perceive certain tastes."

The research team wanted to better understand how temperature and pain intersect with taste neurologically. Building on their previous research that had shown that temperature and taste signals come together in a particular section of the midbrain, Lemon's research group used mouse models under anesthesia to artificially stimulate temperature and pain-related fibers, combined with a physiological method to monitor the actions occurring in the brain to determine the connection between these senses.

"It's been known that temperature and taste can activate some of the same cells in the brain, but this was rarely systematically studied," he said. "We wanted to know if the temperature responses that we were seeing in this part of the brain were actually attributable to activation of thermal and pain-related fibers that innervate the head, face and mouth. To do this we used a modern genetic technology where we could insert a protein into these 'temperature/pain' cells that allowed us to control these cells with blue light -- we could turn the cells on with a light, like a light switch."

"What we found is that these neurons that scientists have studied for a long time as taste neurons actually respond to artificial stimulation of these temperature/pain cells," he added. "This is significant because most scientists that have looked at taste, they're usually only studying neural circuits from the perspective of taste. Pain scientists are usually only looking at pain-related responses, but they actually come together in this part of the midbrain, and not only do they come together, they do so in a very systematic way where preferred tastes and preferred temperatures are separated from adverse taste and temperatures in terms of the way that the responses are happening in this part of the brain."

The researchers categorize preferred or pleasurable tastes as something sweet, like sugar, whereas adverse tastes are bitter -- which can signify that something may be toxic or harmful. Similarly, people, and mice, have preferred temperatures, like a comfortably warmed or cooled environment as compared to an extreme cold or extreme heat stimulus.

Through this artificial stimulation of temperature/pain cells and the corresponding taste neurons, they discovered the brain segregated preferable tastes and temperatures from adverse tastes and temperatures. This finding offers new insights into how these senses interact, which could have implications for how scientists understand the brain's responses to stimuli that cause pain.

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New study gives the most detailed look yet at the neuroscience of placebo effects

 A large proportion of the benefit that a person gets from taking a real drug or receiving a treatment to alleviate pain is due to an individual's mindset, not to the drug itself. Understanding the neural mechanisms driving this placebo effect has been a longstanding question. A meta-analysis published in Nature Communications finds that placebo treatments to reduce pain, known as placebo analgesia, reduce pain-related activity in multiple areas of the brain.

Previous studies of this kind have relied on small-scale studies, so until now, researchers did not know if the neural mechanisms underlying placebo effects observed to date would hold up across larger samples. This study represents the first large-scale mega-analysis, which looks at individual participants' whole brain images. It enabled researchers to look at parts of the brain that they did not have sufficient resolution to look at in the past. The analysis was comprised of 20 neuroimaging studies with 600 healthy participants. The results provide new insight on the size, localization, significance and heterogeneity of placebo effects on pain-related brain activity.

The research reflects the work of an international collaborative effort by the Placebo Neuroimaging Consortium, led by Tor Wager , the Diana L. Taylor Distinguished Professor in Neuroscience at Dartmouth and Ulrike Bingel, a professor at the Center for Translational Neuro- and Behavioral Sciences in the department of neurology at University Hospital Essen, for which Matthias Zunhammer and Tamás Spisák at the University Hospital Essen, served as co-authors. The meta-analysis is the second with this sample and builds on the team's earlier research using an established pain marker developed earlier by Wager's lab.

"Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction," explains co-author Wager, who is also the principal investigator of the Cognitive and Affective Neuroscience Lab at Dartmouth. "We are still learning how the brain constructs pain experiences, but we know it's a mix of brain areas that process input from the body and those involved in motivation and decision-making. Placebo treatment reduced activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain."

Across the studies in the meta-analysis, participants had indicated that they felt less pain; however, the team wanted to find out if the brain responded to the placebo in a meaningful way. Is the placebo changing the way a person constructs the experience of pain or is it changing the way a person thinks about it after the fact? Is the person really feeling less pain?

With the large sample, the researchers were able to confidently localize placebo effects to specific zones of the brain, including the thalamus and the basal ganglia. The thalamus serves as a gateway for sights and sounds and all kinds of sensory motor input. It has lots of different nuclei, which act like processing stations for different kinds of sensory input. The results showed that parts of the thalamus that are most important for pain sensation were most strongly affected by the placebo. In addition, parts of the somatosensory cortex that are integral to the early processing of painful experiences were also affected. The placebo effect also impacted the basal ganglia, which are important for motivation and connecting pain and other experiences to action. "The placebo can affect what you do with the pain and how it motivates you, which could be a larger part of what's happening here," says Wager. "It's changing the circuitry that's important for motivation."

The findings revealed that placebo treatments reduce activity in the posterior insula, which is one of the areas that are involved in early construction of the pain experience. This is the only site in the cortex that you can stimulate and invoke the sense of pain. The major ascending pain pathway goes from parts of the thalamus to the posterior insula. The results provide evidence that the placebo affects that pathway for how pain is constructed.

Prior research has illustrated that with placebo effects, the prefrontal cortex is activated in anticipation of pain. The prefrontal cortex helps keep track of the context of the pain and maintain the belief that it exists. When the prefrontal cortex is activated, there are pathways that trigger opioid release in the midbrain that can block pain and pathways that can modify pain signaling and construction.

The team found that activation of the prefrontal cortex is heterogeneous across studies, meaning that no particular areas in this region were activated consistently or strongly across the studies. These differences across studies are similar to what is found in other areas of self-regulation, where different types of thoughts and mindsets can have different effects. For example, other work in Wager's laboratory has found that rethinking pain by using imagery and storytelling typically activates the prefrontal cortex, but mindful acceptance does not. Placebo effects likely involve a mix of these types of processes, depending on the specifics of how it is given and people's predispositions.

"Our results suggest that placebo effects are not restricted solely to either sensory/nociceptive or cognitive/affective processes, but likely involves a combination of mechanisms that may differ depending on the placebo paradigm and other individual factors," explains Bingel. "The study's findings will also contribute to future research in the development of brain biomarkers that predict an individual's responsiveness to placebo and help distinguish placebo from analgesic drug responses, which is a key goal of the new collaborative research center, Treatment Expectation ."

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Neanderthals may have had a lower threshold for pain

Depiction of early humans, photo concept

Pain is mediated through specialized nerve cells that are activated when potentially harmful things affect various parts of our bodies. These nerve cells have a special ion channel that has a key role in starting the electrical impulse that signals pain and is sent to the brain. According to a new study, people who inherited the Neanderthal variant of this ion channel experience more pain.

As several Neanderthal genomes of high quality are now available researchers can identify genetic changes that were present in many or all Neanderthals, investigate their physiological effects and look into their consequences when they occur in people today. Looking into one gene that carries such changes, Hugo Zeberg, Svante Pääbo and colleagues found that some people, especially from central and south America but also in Europe, have inherited a Neanderthal variant of a gene that encodes an ion channel that initiates the sensation of pain.

By using data from a huge population study in the UK, the authors show that people in the UK who carry the Neanderthal variant of the ion channel experience more pain. "The biggest factor for how much pain people report is their age. But carrying the Neanderthal variant of the ion channel makes you experience more pain similar to if you were eight years older," says lead author Hugo Zeberg, a researcher at the Max Planck Institute for Evolutionary Anthropology and Karolinska Institutet. "The Neanderthal variant of the ion channel carries three amino acid differences to the common, 'modern' variant," explains Zeberg. "While single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying three amino acid substitutions leads to heightened pain sensitivity in present-day people."

On a molecular level, the Neanderthal ion channel is more easily activated which may explain why people who inherited it have a lowered pain threshold. "Whether Neanderthals experienced more pain is difficult to say because pain is also modulated both in the spinal cord and in the brain," says Pääbo. "But this work shows that their threshold for initiating pain impulses was lower than in most present-day humans."

From Science Daily

Scientists find brain center that 'profoundly' shuts down pain

Neurons illustration

A Duke University research team has found a small area of the brain in mice that can profoundly control the animals' sense of pain.

Somewhat unexpectedly, this brain center turns pain off, not on. It's also located in an area where few people would have thought to look for an anti-pain center, the amygdala, which is often considered the home of negative emotions and responses, like the fight or flight response and general anxiety.

"People do believe there is a central place to relieve pain, that's why placebos work," said senior author Fan Wang, the Morris N. Broad Distinguished Professor of neurobiology in the School of Medicine. "The question is where in the brain is the center that can turn off pain."

"Most of the previous studies have focused on which regions are turned ON by pain," Wang said. "But there are so many regions processing pain, you'd have to turn them all off to stop pain. Whereas this one center can turn off the pain by itself."

The work is a follow-up to earlier research in Wang's lab looking at neurons that are activated, rather than suppressed, by general anesthetics. In a 2019 study, they found that general anesthesia promotes slow-wave sleep by activating the supraoptic nucleus of the brain. But sleep and pain are separate, an important clue that led to the new finding, which appears online May 18 in Nature Neuroscience.

The researchers found that general anesthesia also activates a specific subset of inhibitory neurons in the central amygdala, which they have called the CeAga neurons (CeA stands for central amygdala; ga indicates activation by general anesthesia). Mice have a relatively larger central amygdala than humans, but Wang said she had no reason to think we have a different system for controlling pain.

Using technologies that Wang's lab has pioneered to track the paths of activated neurons in mice, the team found the CeAga was connected to many different areas of the brain, "which was a surprise," Wang said.

By giving mice a mild pain stimulus, the researchers could map all of the pain-activated brain regions. They discovered that at least 16 brain centers known to process the sensory or emotional aspects of pain were receiving inhibitory input from the CeAga.

"Pain is a complicated brain response," Wang said. "It involves sensory discrimination, emotion, and autonomic (involuntary nervous system) responses. Treating pain by dampening all of these brain processes in many areas is very difficult to achieve. But activating a key node that naturally sends inhibitory signals to these pain-processing regions would be more robust."

Using a technology called optogenetics, which uses light to activate a small population of cells in the brain, the researchers found they could turn off the self-caring behaviors a mouse exhibits when it feels uncomfortable by activating the CeAga neurons. Paw-licking or face-wiping behaviors were "completely abolished" the moment the light was switched on to activate the anti-pain center.

"It's so drastic," Wang said. "They just instantaneously stop licking and rubbing."

When the scientists dampened the activity of these CeAga neurons, the mice responded as if a temporary insult had become intense or painful again. They also found that low-dose ketamine, an anesthetic drug that allows sensation but blocks pain, activated the CeAga center and wouldn't work without it.

Now the researchers are going to look for drugs that can activate only these cells to suppress pain as potential future pain killers, Wang said.

Read more at Science Daily

Scientists unveil how general anesthesia works

Hailed as one of the most important medical advances, the discovery of general anesthetics -- compounds which induce unconsciousness, prevent control of movement and block pain -- helped transform dangerous and traumatic operations into safe and routine surgery. But despite their importance, scientists still don't understand exactly how general anesthetics work.

Now, in a study published this week in the Journal of Neuroscience, researchers from the Okinawa Institute of Science and Technology Graduate University (OIST) and Nagoya University have revealed how a commonly used general anesthetic called isoflurane weakens the transmission of electrical signals between neurons, at junctions called synapses.

"Importantly, we found that isoflurane did not block the transmission of all electrical signals equally; the anesthetic had the strongest effect on higher frequency impulses that are required for functions such as cognition or movement, whilst it had minimal effect on low frequency impulses that control life-supporting functions, such as breathing," said Professor Tomoyuki Takahashi, who leads the Cellular and Molecular Synaptic Function (CMSF) Unit at OIST. "This explains how isoflurane is able to cause anesthesia, by preferentially blocking the high frequency signals."

At synapses, signals are sent by presynaptic neurons and received by postsynaptic neurons. At most synapses, communication occurs via chemical messengers -- or neurotransmitters.

When an electrical nerve impulse, or action potential, arrives at the end of the presynaptic neuron, this causes synaptic vesicles -- tiny membrane 'packets' that contain neurotransmitters -- to fuse with the terminal membrane, releasing the neurotransmitters into the gap between neurons. When enough neurotransmitters are sensed by the postsynaptic neuron, this triggers a new action potential in the post-synaptic neuron.

The CMSF unit used rat brain slices to study a giant synapse called the calyx of Held. The scientists induced electrical signals at different frequencies and then detected the action potentials generated in the postsynaptic neuron. They found that as they increased the frequency of electrical signals, isoflurane had a stronger effect on blocking transmission.

To corroborate his unit's findings, Takahashi reached out to Dr. Takayuki Yamashita, a researcher from Nagoya University who conducted experiments on synapses, called cortico-cortical synapses, in the brains of living mice.

Yamashita found that the anesthetic affected cortico-cortical synapses in a similar way to the calyx of Held. When the mice were anesthetized using isoflurane, high frequency transmission was strongly reduced whilst there was less effect on low frequency transmission.

"These experiments both confirmed how isoflurane acts as a general anesthetic," said Takahashi. "But we wanted to understand what underlying mechanisms isoflurane targets to weaken synapses in this frequency-dependent manner."

Tracking down the targets

With further research, the researchers found that isoflurane reduced the amount of neurotransmitter released, by both lowering the probability of the vesicles being released and by reducing the maximum number of vesicles able to be released at a time.

The scientists therefore examined whether isoflurane affected calcium ion channels, which are key in the process of vesicle release. When action potentials arrive at the presynaptic terminal, calcium ion channels in the membrane open, allowing calcium ions to flood in. Synaptic vesicles then detect this rise in calcium, and they fuse with the membrane. The researchers found that isoflurane lowered calcium influx by blocking calcium ion channels, which in turn reduced the probability of vesicle release.

"However, this mechanism alone could not explain how isoflurane reduces the number of releasable vesicles, or the frequency-dependent nature of isoflurane's effect," said Takahashi.

The scientists hypothesized that isoflurane could reduce the number of releasable vesicles by either directly blocking the process of vesicle release by exocytosis, or by indirectly blocking vesicle recycling, where vesicles are reformed by endocytosis and then refilled with neurotransmitter, ready to be released again.

By electrically measuring the changes in the surface area of the presynaptic terminal membrane, which is increased by exocytosis and decreased by endocytosis, the scientists concluded that isoflurane only affected vesicle release by exocytosis, likely by blocking exocytic machinery.

"Crucially, we found that this block only had a major effect on high frequency signals, suggesting that this block on exocytic machinery is the key to isoflurane's anesthetizing effect," said Takahashi.

The scientists proposed that high frequency action potentials trigger such a massive influx of calcium into the presynaptic terminal that isoflurane cannot effectively reduce the calcium concentration. Synaptic strength is therefore weakened predominantly by the direct block of exocytic machinery rather than a reduced probability of vesicle release.

Meanwhile, low frequency impulses trigger less exocytosis, so isoflurane's block on exocytic machinery has little effect. Although isoflurane effectively reduces entry of calcium into the presynaptic terminal, lowering the probability of vesicle release, by itself, is not powerful enough to block postsynaptic action potentials at the calyx of Held and has only a minor effect in cortico-cortical synapses. Low frequency transmission is therefore maintained.

Overall, the series of experiments provide compelling evidence to how isoflurane weakens synapses to induce anesthesia.

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Persistent headache or back pain 'twice as likely' in the presence of the other

People with persistent back pain or persistent headaches are twice as likely to suffer from both disorders, a new study from the University of Warwick has revealed.

The results, published in the Journal of Headache and Pain, suggest an association between the two types of pain that could point to a shared treatment for both.

The researchers from Warwick Medical School who are funded by the National Institute for Health Research (NIHR) led a systematic review of fourteen studies with a total of 460,195 participants that attempt to quantify the association between persistent headaches and persistent low back pain. They found an association between having persistent low back pain and having persistent (chronic) headaches, with patients experiencing one typically being twice as likely to experience the other compared to people without either headaches or back pain. The association is also stronger for people affected by migraine.

The researchers focused on people with chronic headache disorders, those who will have had headaches on most days for at least three months, and people with persistent low back pain that experience that pain day after day. These are two very common disorders that are leading causes of disability worldwide.

Around one in five people have persistent low back pain and one in 30 have chronic headaches. The researchers estimate that just over one in 100 people (or well over half a million people) in the UK have both.

Professor Martin Underwood, from Warwick Medical School, said: "In most of the studies we found that the odds were about double -- either way, you're about twice as likely to have headaches or chronic low back pain in the presence of the other. Which is very interesting because typically these have been looked as separate disorders and then managed by different people. But this makes you think that there might be, at least for some people, some commonality in what is causing the problem.

"There may be something in the relationship between how people react to the pain, making some people more sensitive to both the physical causes of the headache, particularly migraine, and the physical causes in the back, and how the body reacts to that and how you become disabled by it. There may also be more fundamental ways in how the brain interprets pain signals, so the same amount of input into the brain may be felt differently by different people.

"It suggests the possibility of an underpinning biological relationship, at least in some people with headache and back pain, that could also be a target for treatment."

Currently, there are specific drug treatments for patients with persistent migraine. For back pain, treatment focuses on exercise and manual therapy, but can also include cognitive behavioural approaches and psychological support approaches for people who are very disabled with back pain. The researchers suggest that those types of behavioural support systems may also help people living with chronic headaches.

Professor Underwood added: "A joint approach would be appropriate because there are specific treatments for headaches and people with migraine. Many of the ways we approach chronic musculoskeletal pain, particularly back pain, are with supportive management by helping people to live better with their pain.

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Insects feel persistent pain after injury, evidence suggests

Fruit fly

Scientists have known insects experience something like pain since 2003, but new research published today from Associate Professor Greg Neely and colleagues at the University of Sydney proves for the first time that insects also experience chronic pain that lasts long after an initial injury has healed.

The study in the peer-reviewed journal Science Advances offers the first genetic evidence of what causes chronic pain in Drosophila (fruit flies) and there is good evidence that similar changes also drive chronic pain in humans. Ongoing research into these mechanisms could lead to the development of treatments that, for the first time, target the cause and not just the symptoms of chronic pain.

"If we can develop drugs or new stem cell therapies that can target and repair the underlying cause, instead of the symptoms, this might help a lot of people," said Associate Professor Neely, whose team of researchers is studying pain at the Charles Perkins Centre with the goal of developing non-opioid solutions for pain management.

Pain and insects

"People don't really think of insects as feeling any kind of pain," said Associate Professor Neely. "But it's already been shown in lots of different invertebrate animals that they can sense and avoid dangerous stimuli that we perceive as painful. In non-humans, we call this sense 'nociception', the sense that detects potentially harmful stimuli like heat, cold, or physical injury, but for simplicity we can refer to what insects experience as 'pain'."

"So we knew that insects could sense 'pain', but what we didn't know is that an injury could lead to long lasting hypersensitivity to normally non-painful stimuli in a similar way to human patients' experiences."

What is chronic pain?

Chronic pain is defined as persistent pain that continues after the original injury has healed. It comes in two forms: inflammatory pain and neuropathic pain.

The study of fruit flies looked at neuropathic 'pain', which occurs after damage to the nervous system and, in humans, is usually described as a burning or shooting pain. Neuropathic pain can occur in human conditions such as sciatica, a pinched nerve, spinal cord injuries, postherpetic neuralgia (shingles), diabetic neuropathy, cancer bone pain, and in accidental injuries.

Testing pain in fruit flies

In the study, Associate Professor Neely and lead author Dr Thang Khuong from the University's Charles Perkins Centre, damaged a nerve in one leg of the fly. The injury was then allowed to fully heal. After the injury healed, they found the fly's other legs had become hypersensitive. "After the animal is hurt once badly, they are hypersensitive and try to protect themselves for the rest of their lives," said Associate Professor Neely. "That's kind of cool and intuitive."

Next, the team genetically dissected exactly how that works.

"The fly is receiving 'pain' messages from its body that then go through sensory neurons to the ventral nerve cord, the fly's version of our spinal cord. In this nerve cord are inhibitory neurons that act like a 'gate' to allow or block pain perception based on the context," Associate Professor Neely said. "After the injury, the injured nerve dumps all its cargo in the nerve cord and kills all the brakes, forever. Then the rest of the animal doesn't have brakes on its 'pain'. The 'pain' threshold changes and now they are hypervigilant."

"Animals need to lose the 'pain' brakes to survive in dangerous situations but when humans lose those brakes it makes our lives miserable. We need to get the brakes back to live a comfortable and non-painful existence."

In humans, chronic pain is presumed to develop through either peripheral sensitisation or central disinhibition, said Associate Professor Neely. "From our unbiased genomic dissection of neuropathic 'pain' in the fly, all our data points to central disinhibition as the critical and underlying cause for chronic neuropathic pain."

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