Category: Pain Management

Categories : Genetics Pain ManagementTags :

Neanderthal Gene Variants Associated with Greater Sensitivity to Some Types of Pain

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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 measured the pain thresholds of 1963 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 5971 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.

Diagram comparing the nose shape of a Neanderthal with that of a modern human by Dr Macarena Fuentes-Guajardo.

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.”

First author Dr Pierre Faux (Aix-Marseille University and University of Toulouse) said: “We have shown how variation in our genetic code can alter how we perceive pain, including genes that modern humans acquired from the Neanderthals. But genes are just one of many factors, including environment, past experience, and psychological factors, which influence pain.”

Source: University College London

Categories : COVID Pain ManagementTags :

Does COVID Infection or Vaccination Worsen Migraines?

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Headaches are a frequent complaint of those with a COVID infection, or have received a COVID vaccination, and it is thought that it may subsequently increase the frequency of migraines. To put this to the test, an observational study published in the European Journal of Neurology investigated the effects on migraine frequency of having had either been infected with COVID or having received a COVID vaccination.

Among 550 adults who had received migraine-related care at a Spanish headache clinic, 44.9% (247) reported COVID at least once and 83.3% (458) had been vaccinated; 61 patients (24.7%) reported migraine worsening since COVID and 52 (11.4%) since vaccination.

In participants who perceived that their migraines worsened, those who had been infected were 2.5-times more likely to be concerned about migraine worsening and patients who had been vaccinated were 17.3-times more likely to have this concern.

When investigators examined patients’ e-diary information, they observed no significant difference in headache frequency one month before and after infection or vaccination, even when comparing patients with and without self-reported migraine worsening.

“In the case of COVID-19, we reported previously that indeed headache is a frequent and disabling symptom of the infection; yet, it may not necessarily be linked to an increase in migraine frequency,” the authors wrote. “In light of our results, we believe that clinicians should deliver to patients a more reassuring message that COVID-19 and COVID-19 vaccines may marginally affect migraine course and that probably the impact of the infection and vaccines is less than the individual rhythmicity to have attacks. This information may help minimise their worry.”

Source: Wiley

Categories : Pain ManagementTags :

Chronic Back Pain may be Easier to Treat if it’s ‘in the Brain’

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One therapy for chronic back pain is to teach patients how to ‘reprocess’ it in the brain. Now, this therapy may become even more effective thanks a study published in JAMA Network Open. The study examined the critical connection between the brain and pain for treating chronic pain. Specifically, they looked at the importance of pain attributions, which are people’s beliefs about the underlying causes of their pain, to reduce chronic back pain severity. Understanding the source of the pain may help some to avoid surgery which may be ineffective or even worsen the pain.

“Millions of people are experiencing chronic pain and many haven’t found ways to help with the pain, making it clear that something is missing in the way we’re diagnosing and treating people,” said the study’s first author Yoni Ashar, PhD, assistant professor of internal medicine at the University of Colorado Anschutz Medical Campus.

Pain is often in the brain

Ashar and his team tested whether the reattribution of pain to mind or brain processes was associated with pain relief in pain reprocessing therapy (PRT), which teaches people to perceive pain signals sent to the brain as less threatening. Their goal was to better understand how people recovered from chronic back pain. The study revealed after PRT, patients reported reduced back pain intensity.

“Our study shows that discussing pain attributions with patients and helping them understand that pain is often ‘in the brain’ can help reduce it,” Ashar said.

To study the effects of pain attributions, they enrolled over 150 adults experiencing moderately severe chronic back pain in a randomised trial to receive PRT. They found that two-thirds of people treated with PRT reported being pain-free or nearly so after treatment, compared to only 20% of placebo controls.

“This study is critically important because patients’ pain attributions are often inaccurate. We found that very few people believed their brains had anything to do with their pain. This can be unhelpful and hurtful when it comes to planning for recovery since pain attributions guide major treatment decisions, such as whether to get surgery or psychological treatment,” said Ashar.

Before PRT treatment, only 10% of participants’ attributions of PRT treatment were mind- or brain-related. However, after PRT, this increased to 51%. The study revealed that the more participants shifted to viewing their pain as due to mind or brain processes, the greater the reduction in chronic back pain intensity they reported.

The role of discussing brain drivers of chronic pain 

“These results show that shifting perspectives about the brain’s role in chronic pain can allow patients to experience better results and outcomes,” Ashar adds.

Ashar says that one reason for this may be that when patients understand their pain as due to brain processes, they learn that there is nothing wrong with their body and that the pain is a ‘false alarm’ being generated by the brain that they don’t need to be afraid of.

The researchers hope this study will encourage providers to talk to their patients about the reasons behind their pain and discuss causes outside of biomedical ones.

“Often, discussions with patients focus on biomedical causes of pain. The role of the brain is rarely discussed,” said Ashar. “With this research, we want to provide patients as much relief as possible by exploring different treatments, including ones that address the brain drivers of chronic pain.”

Source: University of Colorado Anschutz Medical Campus

Categories : Paediatrics Pain ManagementTags :

Children’s ‘Growing Pains’ may be Tied to Migraines

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New research published in the journal Headache reveals that, in children and adolescents, pain in the lower limbs – what are often called “growing pains” by clinicians and are commonly attributed to rapid growth – may indicate the presence or risk of migraines.

The study included 100 children and adolescents born to mothers with migraines seen at a headache clinic, with half of the youth experiencing growing pains.

“In families of children with growing pains, there is an increased prevalence of other pain syndromes, especially migraine among parents,” the authors wrote. “On the other hand, children with migraine have a higher prevalence of growing pains, suggesting a common pathogenesis; therefore, we hypothesised that growing pains in children are a precursor or comorbidity with migraine.”

After five years of follow-up, 78 patients completed the study, of which 42 were from the group that experienced growing pains and 36 were from the control group. Headaches occurred in 76% of participants who had growing pains and in 22% of controls. Growing pains persisted in 14% of participants who had growing pains at the start of the study and appeared in 39% of participants who were previously asymptomatic.

“Pain in the lower limbs of children and adolescents… may reflect a precursor or comorbidity with migraine,” the authors concluded.

Source: Wiley

Categories : Pain ManagementTags :

‘Scrambler’ Therapy May Offer Lasting Relief for Chronic Pain, Review Paper Suggests

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A new review paper published in The New England Journal of Medicine suggests that scrambler therapy, a noninvasive pain treatment, can yield significant relief for 80–90% of patients with chronic pain, and it may be more effective than another noninvasive therapy: transcutaneous electrical nerve stimulation (TENS).

Scrambler therapy administers electrical stimulation through the skin via electrodes placed in areas of the body above and below where chronic pain is felt. The goal is to capture the nerve endings and replace signals from the area experiencing pain with signals coming from adjacent areas experiencing no pain, thereby ‘scrambling’ the pain signals sent to the brain, explains the study’s primary author, Thomas Smith, MD, a professor of oncology and medicine at the Johns Hopkins University School of Medicine.

All chronic pain and almost all nerve and neuropathic pain result from two things: pain impulses coming from damaged nerves that send a constant barrage up to pain centers in the brain, and the failure of inhibitory cells to block those impulses and prevent them from becoming chronic, says Smith, who also is the director of palliative medicine for Johns Hopkins Medicine.

Constantly hitting the reset button on pain

“If you can block the ascending pain impulses and enhance the inhibitory system, you can potentially reset the brain so it doesn’t feel chronic pain nearly as badly,” Smith says. “It’s like pressing Control-Alt-Delete about a billion times.”

Many patients “get really substantial relief that can often be permanent,” he says. They receive from three to 12 half-hour sessions.

As a physician who treats chronic pain, Smith says, “Scrambler therapy is the most exciting development I have seen in years – it’s effective, it’s noninvasive, it reduces opioid use substantially and it can be permanent.”

Source: John Hopkins Medicine

Categories : Neurodegenerative Diseases Pain ManagementTags :

Alzheimer’s Patients have an Altered Perception of Pain

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New research published in Nature Communications has found that in a mouse model mimicking Alzheimer’s Disease (AD) pain signals are not processed in the same way as in healthy mice. The research, from King’s College London, suggests that the perception of pain in people with Alzheimer’s Disease may be altered, and asks whether changes in management of pain in people with AD could improve their quality of life.

While chronic musculoskeletal pain is common in individuals with AD, it remains largely untreated as it can go unreported due to the cognitive deficits attached to the disease.

In this study, the researchers sought to explore whether there is also an alteration in the body’s response to pain by the nervous system in people with AD.

In healthy mice, pain signals are transmitted from the point of origin to the central nervous system to initiate an immune response. The protein Galectin-3 has been demonstrated to be responsible for pain signal transmission to the spinal cord. Upon reaching the spinal cord, it binds to another protein, TLR4, to initiate the immune response.

In this study, researchers used an AD mice model and gave them rheumatoid arthritis, a type of chronic inflammatory disease, through blood transfer. They observed an increase in allodynia, pain caused by a stimulus that doesn’t normally provoke pain, as a response to the inflammation. They also saw increased activation of a microglia in the spinal cord. They determined that these effects were regulated by TLR4.

Researchers found that the mice with AD lacked TLR4 in the immune cells of their central nervous system and were therefore unable to respond to pain in the typical way as the signals were not being perceived.

This resulted in the mice with AD developing less joint inflammation related pain, and a less powerful immune cell response to the pain signals received by the central nervous system.

Professor Marzia Malcangio, Professor of Neuropharmacology at King’s IoPPN and the study’s senior author said, “Nociceptive pain – pain which is the result of tissue damage – is the second most prevalent comorbidity in individuals with Alzheimer’s disease. Our study has shown that, in mice with Alzheimer’s, the body’s ability to process that pain is altered due to the lack of TLR4; a protein vital to the immune response process in the central nervous system.

“These are important findings, as untreated pain can contribute to the psychiatric symptoms of the disease. Increasing our understanding of this area could, with more research, lead to more effective treatments and ultimately improve people’s quality of life.”

George Sideris-Lampretsas, a PhD student at King’s IoPPN and the study’s first author said, “The results of this study have the potential to make an impact, not only by identifying Galectin-3/TLR4 as a potential therapeutic target for chronic pain, but most importantly by raising awareness around the underreported and untreated pain experienced by patients with AD.”

Source: King’s College London

Categories : Injury & Trauma Pain ManagementTags :

Antihypertensive Drug Prazosin could Relieve Posttraumatic Headaches

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Researchers have shown that the antihypertensive drug prazosin can prevent posttraumatic headaches, such as those caused by a concussion suffered by members of the military. Their findings were published in Headache: The Journal of Head and Face Pain.

Senior study author Dr Murray Raskind explained that few treatment options exist for this type of headache: “Persistent posttraumatic headaches are the most common long-term consequence of mild traumatic brain injuries (concussions) in Veterans and active-duty service members, causing substantial distress and disability at home and work. Although these headaches usually resemble migraine headaches symptomatically, they often fail to respond to the prevention treatments useful for migraines.”

The FDA approved prazosin to treat hypertension in 1976. It has been widely used off-label to treat conditions such as PTSD-associated nightmares and enlarged prostate. An earlier study by members of the research group suggested that prazosin could reduce the frequency and severity of headaches caused by traumatic brain injury (TBI).

To test this effect, researchers led by VA Puget Sound Health Care System conducted a pilot study with 48 Veterans and service members with headaches caused by mild TBI, also known as a concussion. Participants took gradually increasing doses of prazosin for five weeks before receiving the maximum dose for 12 weeks. The study showed that the drug was well-tolerated, and researchers reported that morning drowsiness was the only adverse effect.

Before the trial began, study participants had an average of 18 headache days each month. By the end of the 12-week period, those taking prazosin only had headaches for an average of six days a month. Participants receiving a placebo reported some reduction in headaches, but still had headaches about 12 days a month. Significantly more participants in the prazosin group had at least 50% fewer headaches during the 12 weeks of taking a full dose of medication.

Participants taking prazosin also saw significant decreases in how much headaches impacted their quality of life. By the end of the trial, those taking prazosin reported that headaches had “some impact” on their daily ability to function, while participants given a placebo continued to report “severe impact” of headaches.

Larger clinical trials are needed to confirm the extent of these promising results, according to the researchers, but these initial findings offer a potential relief for a common ailment faced by many Veterans.

“This study is the only clinical trial of an oral medication to demonstrate efficacy for posttraumatic headache. Because prazosin is widely used across VA and the Department of Defense to treat PTSD trauma nightmares and sleep disruption, many VA and DOD prescribers are familiar with prescribing this generically available, inexpensive medication,” said Raskind. “Prazosin now offers an evidence-based approach to alleviate the suffering of Veterans and service members who have struggled for years with frequent posttraumatic headaches.”

Source: Veterans Affair Research Communications

Categories : Genetics Pain ManagementTags :

The Molecular Secrets of the ‘Feel No Pain’ Gene

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The biology underpinning a rare genetic mutation that allows its carrier to feel almost no pain, heal faster and had reduced anxiety and fear, has been uncovered in a new study published in Brain.

Though it may sound like the stuff of superheroes, the carrier of the genetic mutation is an ordinary Scottish woman named Jo Cameron, who was first referred to pain geneticists at University College London in 2013, after her doctor noticed that she experienced no pain after major surgeries on her hip and hand. In 2019, they identified a new gene that they appropriately named FAAH-OUT, which had a rare genetic mutation. In combination with another, more common mutation in FAAH, it was found to be the cause of Jo’s unique characteristics.

The new research describes how the mutation in FAAH-OUT ‘turns down’ FAAH gene expression, as well as the knock-on effects on other molecular pathways linked to wound healing and mood. It is hoped the findings will lead to new drug targets and open up new avenues of research in these areas.

The area of the genome containing FAAH-OUT had previously been assumed to be ‘junk’ DNA that had no function, but it was found to mediate the expression of FAAH, a gene that is part of the endocannabinoid system and that is well-known for its involvement in pain, mood and memory.

In this study, the team from UCL sought to understand how FAAH-OUT works at a molecular level, the first step towards being able to take advantage of this unique biology for applications like drug discovery.

This included a range of approaches, such as CRISPR-Cas9 experiments on cell lines to mimic the effect of the mutation on other genes, as well as analysing the expression of genes to see which were active in molecular pathways involved with pain, mood and healing.

The team observed that FAAH-OUT regulates the expression of FAAH. When it is significantly turned down as a result of the mutation carried by Jo Cameron, FAAHenzyme activity levels are significantly reduced.

Dr Andrei Okorokov (UCL Medicine), a senior author of the study, said: “The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map. As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I think these findings will have important implications for areas of research such as wound healing, depression and more.”

The authors looked at fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways. While the mutations that Jo Cameron carries turn down FAAH, they also found a further 797 genes that were turned up and 348 that were turned down. This included alterations to the WNT pathway that is associated with wound healing, with increased activity in the WNT16 gene that has been previously linked to bone regeneration.

Two other key genes that were altered were BDNF, which has previously been linked to mood regulation and ACKR3, which helps to regulate opioid levels. These gene changes may contribute to Jo Cameron’s low anxiety, fear and painlessness.

Senior study author Professor James Cox said: “The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a eureka moment and hugely exciting, but these current findings are where things really start to get interesting. By understanding precisely what is happening at a molecular level, we can start to understand the biology involved and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients.”

Source: University College London

Categories : Pain ManagementTags :

Evidence is Lacking for Most Antidepressants Prescribed for Chronic Pain

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Most antidepressants used for chronic pain are being prescribed with “insufficient” evidence of their effectiveness, scientists have warned. A major investigation into medications used to manage long-term pain found that harms of many of the commonly recommended drugs have not been well studied.

In a Cochrane review, scientists examined 176 trials consisting of nearly 30 000 patients involved in assessments which prescribed antidepressants for chronic pain.

Among the drugs studied were amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine – with only the latter showing reliable evidence for pain relief. One third of people globally are living with chronic pain, World Health Organization data shows, with many prescribed antidepressants for relieving symptoms.

Lead author Professor Tamar Pincus from the University of Southampton said: “This is a global public health concern. Chronic pain is a problem for millions who are prescribed antidepressants without sufficient scientific proof they help, nor an understanding of the long-term impact on health.

“Our review found no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for their safety for chronic pain at any point. Though we did find that duloxetine provided short-term pain relief for patients we studied, we remain concerned about its possible long-term harm due to the gaps in current evidence.”

Amitriptyline is one of the most commonly prescribed antidepressants for pain management worldwide. In the last 12 months, around 10 million prescriptions were given to patients in England at the 10mg dose recommended for pain. By comparison, five million prescriptions were given at the higher doses recommended for depression.

For duloxetine, three and a half million prescriptions were dispensed in England, but the recommended doses do not currently differ between conditions.

The two-year Cochrane study was the largest ever assessment of antidepressants recommended by leading bodies including the UK’s National Institute for Health and Care Excellence (NICE) and the Food and Drug Administration (FDA) in the USA.

Statistician Gavin Stewart, review co-author from Newcastle University, said: “We are calling on governing health bodies NICE and the FDA to update their guidelines to reflect the new scientific evidence, and on funders to stop supporting small and flawed trials. Evidence synthesis is often complex and nuanced but the evidence underpinning the use of these treatments is not equivalent, so current treatment modalities are hard to justify.”

The review revealed that duloxetine was consistently the highest-rated medication and was equally as effective for fibromyalgia, musculoskeletal, and neuropathic pain conditions.

Other results showed:

  • Standard doses of duloxetine are as successful for reducing pain as higher quantities,
  • Milnacipran was also effective at reducing pain, but scientists are not as confident as duloxetine due to fewer studies with fewer people.

Prof Tamar Pincus added: “We simply cannot tell about other antidepressants because sufficiently good studies are not available – but it does not mean that people should stop taking prescribed medication without consulting their GP.”

Scientists responsible for the review, funded by the NIHR’s Health Technology Assessment programme, were from the universities of Southampton, Newcastle, Bristol, UCL, Bath, and Keele, alongside Oxford University Hospital.

The team assessed the trials using a statistical method that enables researchers to combine data from relevant studies to estimate the effects of different drugs, which have not been compared directly in individual trials.

University of Southampton researcher Dr Hollie Birkinshaw said: “Though previous investigations show that some antidepressants might relieve pain, there has never been a comprehensive study examining all medications across all chronic conditions – until now.

“The only reliable evidence is for duloxetine. Adopting a person-centred approach is critical to treatment, and when patients and clinicians decide together to try antidepressants they should start from the drug for which there is good evidence.”

Source: University of Southampton

Categories : Pain ManagementTags :

Avoiding Addiction and Hallucination in the Quest for New Anaesthetics

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Strategies to treat pain without triggering dangerous side effects such as euphoria and addiction have proven elusive. For decades, scientists have attempted to develop drugs that selectively activate one type of opioid receptor to treat pain while not activating another type of opioid receptor linked to addiction. Unfortunately, those compounds can cause a different unwanted effect: hallucinations. But a new study published in the journal Nature has identified a potential route to pain relief that neither triggers addiction nor activates the pathway that causes hallucinations.

Painkilling drugs such as morphine and oxycodone, as well as illegal street drugs such as heroin and fentanyl, activate what are known as mu opioid receptors on nerve cells. Those receptors relieve pain but also cause euphoria, contributing to addiction. An alternative strategy is to target another opioid receptor, called the kappa opioid receptor. Scientists attempting to make drugs that target only the kappa receptor have found that they also effectively relieve pain, but they can be associated with other side effects such as hallucinations.

Research led by Washington University School of Medicine in St. Louis has identified the potential mechanisms behind such hallucinations, with the goal of developing painkillers without this side effect. Using electron microscopes, the researchers identified the way that a natural compound related to the salvia plant selectively binds only to the kappa receptor but then causes hallucinations.

“Since 2002, scientists have been trying to learn how this small molecule causes hallucinations through kappa receptors,” said principal investigator Tao Che, PhD, an assistant professor of anesthesiology. “We determined how it binds to the receptor and activates potential hallucinogenic pathways, but we also found that other binding sites on the kappa receptor don’t lead to hallucinations.”

Developing new drugs to target these other kappa receptor binding sites may relieve pain without either the addictive problems associated with older opioids or the hallucinations associated with the existing drugs that selectively target the kappa opioid receptor.

Targeting the kappa receptor to block pain without hallucinations would be an important step forward, according to Che, because opioid drugs that interact with the mu opioid receptor have led to the current opioid epidemic, causing more than 100 000 overdose deaths in the US in 2021.

“Opioids, especially synthetic opioids such as fentanyl, have contributed to far too many overdose deaths,” Che said. “There’s no doubt we need safer pain-relieving drugs.”

Che’s team, led by first author Jianming Han, PhD, a postdoctoral research associate in Che’s laboratory, found that a class of signaling proteins called G proteins cause the kappa opioid receptor to activate several different pathways.

“There are seven G proteins linked to the kappa receptor, and although they are very similar to each other, the differences between the proteins may help explain why some compounds can cause side effects such as hallucinations,” Han said. “By learning how each of the proteins binds to the kappa receptor, we expect to find ways to activate that receptor without causing hallucinations.”

The function of the G proteins has largely been unclear until now, particularly the protein that activates the pathway lined to hallucinations.

“All of these proteins are similar to one another, but the specific protein subtypes that bind to the kappa receptor determine which pathways will be activated,” Che said. “We have found that the hallucinogenic drugs can preferentially activate one specific G protein but not other, related G proteins, suggesting that beneficial effects such as pain relief can be separated from side effects such as hallucinations. So we expect it will be possible to find therapeutics that activate the kappa receptor to kill pain without also activating the specific pathway that causes hallucinations.”

Source: Washington University School of Medicine