A breakthrough study from the Hebrew University of Jerusalem, published this week in the prestigious journal PNAS (Proceedings of the National Academy of Sciences USA), reveals a previously unknown peripheral mechanism by which paracetamol relieves pain.
The study was led by Prof Alexander Binshtok from the Hebrew University’s Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof Avi Priel from its School of Pharmacy. Together, they uncovered a surprising new way that paracetamol, one of the world’s most common painkillers, actually works.
For decades, scientists believed that paracetamol relieved pain by working only in the brain and spinal cord. But this new research shows that the drug also works outside the brain, in the nerves that first detect pain.
Their discovery centres on a substance called AM404, which the body makes after taking paracetamol. The team found that AM404 is produced right in the pain-sensing nerve endings – and that it works by shutting off specific channels (called sodium channels) that help transmit pain signals. By blocking these channels, AM404 stops the pain message before it even starts.
“This is the first time we’ve shown that AM404 works directly on the nerves outside the brain,” said Prof Binshtok. “It changes our entire understanding of how paracetamol fights pain.”
This breakthrough could also lead to new types of painkillers. Because AM404 targets only the nerves that carry pain, it may avoid the numbness, muscle weakness, and side effects that come with traditional local anaesthetics.
“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,” added Prof Priel.
An experimental drug developed at Duke University School of Medicine could offer powerful pain relief without the dangerous side effects of opioids.
Called SBI-810, the drug is part of a new generation of compounds designed to target a receptor on the nerves and spinal cord. While opioids flood multiple cellular pathways indiscriminately, SBI-810 takes a more focused approach, activating only a specific pain-relief pathway that avoids the euphoric “high” linked to addiction.
In tests in mice, SBI-810 worked well on its own and, when used in combination, made opioids more effective at lower doses, according to the study published in Cell.
Even more encouraging: it prevented common side effects like constipation and buildup of tolerance, which often forces patients to need stronger and more frequent doses of opioids over time.
SBI-810 is in early development, but Duke researchers are aiming for human trials soon and have secured multiple patents for the discovery.
There’s an urgent need for non-opioid pain relievers. Researchers said the drug could be a safer option for treating both short-term and chronic pain for those recovering from surgery or living with diabetic nerve pain.
SBI-810 is designed to target the brain receptor neurotensin receptor 1. Using a method known as biased agonism, it switches on a specific signal – β-arrestin-2 – linked to pain relief, while avoiding other signals that can cause side effects or addiction.
“The receptor is expressed on sensory neurons and the brain and spinal cord,” Ji said. “It’s a promising target for treating acute and chronic pain.”
SBI-810 effectively relieved pain from surgical incisions, bone fractures, and nerve injuries better than some existing painkillers. When injected in mice, it reduced signs of spontaneous discomfort, such as guarding and facial grimacing.
Duke scientists compared SBI-810 to oliceridine, a newer type of opioid used in hospitals, and found SBI-810 worked better in some situations, with fewer signs of distress.
Unlike opioids like morphine, SBI-810 didn’t cause tolerance after repeated use. It also outperformed gabapentin, a common drug for nerve pain, and didn’t cause sedation or memory problems, which are often seen with gabapentin.
Researchers said the compound’s dual action – on both the peripheral and central nervous systems– could offer a new kind of balance in pain medicine: powerful enough to work, yet specific enough to avoid harm.
An animated jellyfish floats through water in the PainWaive game.
Image: PainWaive
The first trial of an interactive game that trains people to alter their brain waves has shown promise as a treatment for nerve pain – offering hope for a new generation of drug-free treatments.
You’re staring at a jellyfish drifting through inky black water on a screen. As your mind calms, the water turns turquoise. Nothing else seems to change, but the headset you’re wearing has picked up a subtle shift in your brainwaves and the game responds by altering the imagery. Now, for the first time, you can see your brain activity change. And by seeing it, you can practice making it happen again.
The game is part of PainWaive, a drug-free treatment for nerve pain developed by UNSW. Combining a game-like app and a brain-monitoring headset, PainWaive teaches users how to regulate the abnormal brain activity linked to chronic nerve pain, offering a potential in-home, non-invasive alternative to opioids.
The study compared hundreds of measures across participants’ pain and related issues like pain interference before, during and after four weeks of interactive game play. Their brain activity was tracked via EEG (electroencephalogram) headsets, with the app responding in real time to shifts in brainwave patterns.
Three out of the four participants showed significant reductions in pain, particularly nearing the end of the treatment. Overall, the pain relief achieved by the three was comparable to or greater than that offered by opioids.
“Restrictions in the study’s size, design and duration limit our ability to generalise the findings or rule out placebo effects,” Dr Hesam-Shariati says.
“But the results we’ve seen are exciting and give us confidence to move to the next stage and our larger trial.”
The PainWaive project builds on UNSW Professor Sylvia Gustin’s seminal research into changes in the brain’s thalamus – a central relay hub in the brain – associated with nerve (neuropathic) pain.
“The brainwaves of people with neuropathic pain show a distinct pattern: more slow theta waves, fewer alpha waves, and more fast, high beta waves,” Prof. Gustin says.
“We believe these changes interfere with how the thalamus talks to other parts of the brain, especially the sensory motor cortex, which registers pain.
“I wondered, can we develop a treatment that directly targets and normalises these abnormal waves?”
The challenge was taken up by an interdisciplinary team at UNSW Science and Neuroscience Research Australia (NeuRA), led by Prof. Gustin and Dr Hesam-Shariati, and resulted in PainWaive.
The four participants in its first clinical trial received a kit with a headset and a tablet preloaded with the game app, which includes directions for its use. They were also given tips for different mental strategies, like relaxing or focusing on happy memories, to help bring their brain activity into a more “normal” state.
The user data, meanwhile, was uploaded to the research team for remote monitoring.
“After just a couple of Zoom sessions, participants were able to run the treatment entirely on their own,” says Dr Hesam-Shariati.
“Participants felt empowered to manage their pain in their own environment. That’s a huge part of what makes this special.”
Initially, Dr Hesam-Shariati says, the team planned to use existing commercial EEG systems, but they were either too expensive or didn’t meet the quality needed to deliver the project. Instead, they developed their own.
“Everything except the open-source EEG board was built in-house,” says Dr Hesam-Shariati. “And soon, even that will be replaced by a custom-designed board.”
Thanks to 3D printing, Prof. Gustin says, the team has cut the cost of each headset to around $300 – a fraction of the $1000 to $20 000 price tags of existing systems.
The headset uses a saline-based wet electrode system to improve signal quality and targets the sensorimotor cortex.
“We’ve worked closely with patients to ensure the headset is lightweight, comfortable, and user-friendly,” says Prof. Gustin.
“Owning the technology offers us the potential to one day offer PainWaive as a truly affordable, accessible solution for at-home pain management, especially for those with limited access to traditional treatments.”
The team is currently focussed on a randomised controlled trial of the PainWaive technology, aiming to recruit 224 people with nerve pain following spinal cord injury.
It’s part of more than a dozen active collaborations between UNSW Science and the Centre for Pain IMPACT at NeuRA, all building on Prof. Gustin’s foundational research into the brain.
Among these is a clinical trial of an eHealth therapy, called Pain and Emotion Therapy, that was shown to reduce chronic pain by retraining the brain to process emotions more effectively.
Another major project, Project Avatar, is inspired by Prof Gustin’s discovery that half of people with complete spinal cord injuries still have touch signals reaching the brain – though the brain can’t identify them.
The trial uses immersive virtual reality and real-world touch stimulation to help the brain relearn how to feel.
“Many of our team are clinician-scientists, and we’re focused on developing practical treatments that can be integrated into the healthcare system,” says Prof Gustin.
“It’s incredibly inspiring to see results that help unlock the brain’s potential to heal itself and bring back hope to people living with pain.”
The researchers are now calling for participants to register their interest in two upcoming trials of the neuromodulation technology: The Spinal Pain Trial, investigating its potential to reduce chronic spinal pain, and the StoPain Trial, exploring its use in treating chronic neuropathic pain in people with a spinal cord injury.
Migraines can severely affect the quality of life for people who suffer from them, making work, social interactions, and even simple tasks unimaginably difficult. With an estimated 15%* of the global population affected, the impact of migraines on daily life and productivity is significant and cannot be underestimated.
“Migraines are more than just headaches — they are complex neurological events that can significantly impact daily life, often leading to missed days of work or school because of the intense pain and other associated symptoms,” says neurologist Dr Michael Huth, President of the South African Headache Society and Executive Board member of the Neurological Association of South Africa, who practises at Netcare Linksfield Hospital.
“The debilitating and wide-ranging symptoms people experience with migraines can reduce productivity. In addition to brain fog and fatigue, some have sensitivity to environmental factors, such as bright lights, strong smells, or loud noises, which can worsen symptoms.
“Furthermore, the emotional distress of dealing with chronic pain from recurring migraines can contribute to anxiety and depression for some individuals who endure them, underlining the importance of proper diagnosis and appropriate management of migraines,” he says.
“While many people think of migraines as intense head pain, there are different types of migraines, each with characteristic symptoms, duration, and triggers. Determining what type of migraine a person is experiencing is key to establishing what can be done to help manage the episodes effectively and, where possible, prevent them.”
Types of migraines generally fall into two broad categories, depending on whether there is a visual or sensory disturbance known as an ‘aura’ before or during the headache phase. “An aura can be described as flashing lights, blind spots, tingling sensations, or difficulty speaking, and a classic migraine includes aura symptoms for 20 minutes to an hour,” Dr Huth explains.
“A migraine without an aura is known as a common migraine. Symptoms include throbbing or pulsating pain often felt on one side of the head, nausea, vomiting, and sensitivity to light and sound.
“These migraines typically last between four and 72 hours without treatment, and frequency varies with some people experiencing occasional attacks, known as episodic migraine, while others may experience repeated migraines many times in a month.
“Chronic migraine is defined as symptoms occurring for 15 days or more per month for at least three months. These migraines are persistent and can be near-daily in severe cases,” he says.
“Hemiplegic migraine, which is often caused by genetic factors, is experienced as temporary weakness or paralysis on one side of the body, lasting anywhere from a few hours to several days at a time. This type of migraine is accompanied by aura symptoms such as confusion, speech difficulties, or dizziness. While the attacks are usually infrequent, some individuals experience hemiplegic migraine multiple times a year.”
In addition to these more widely recognised migraines, Dr Huth warns that some lesser-known types can be just as disruptive.
“Vestibular migraine, also known as migraine-associated vertigo, involves symptoms of dizziness, balance issues, nausea, and sensitivity to movement – sometimes without a headache – lasting from minutes to hours. Lifestyle changes can be helpful in conjunction with vestibular rehabilitation therapy to improve balance and stability and prescribed treatment such as beta-blockers or anti-seizure medication.
“Abdominal migraines, on the other hand, are recurrent episodes of severe stomach pain, nausea, and vomiting, usually seen in children. Often, adjusting lifestyle factors and drinking enough water for good hydration can help to prevent or minimise abdominal migraines, supported with medication where needed,” Dr Huth says.
“Ophthalmic or retinal migraine symptoms include temporary loss of vision or visual disturbances in one eye, followed by or accompanied by a headache. It is important that people experiencing this type of migraine have an eye examination with their ophthalmologist to rule out the possibility of other eye-related conditions that could be contributing to the condition. Identifying and avoiding triggers can be helpful, as well as migraine-specific medications guided by your treating doctor.”
Tips to reduce migraine frequency and severity
“While medication can help manage migraines, the following lifestyle changes can play a crucial role in reducing their frequency and intensity,” he advises.
1. Maintain a consistent routine
Stick to regular sleeping patterns, aiming for seven to nine hours of rest.
Eat balanced meals at the same times each day to prevent blood sugar levels from dropping.
Stay hydrated, as dehydration is a common migraine trigger.
2. Manage stress
Practise relaxation techniques like meditation, deep breathing, or yoga.
Take breaks from screens and limit exposure to bright or flickering lights.
3. Exercise in moderation
Low-impact activities like walking, swimming, or stretching can help.
Avoid overexertion, as intense workouts can sometimes trigger migraines.
4. Watch your diet
Keep a migraine diary to help identify and avoid triggers.
Common food triggers include caffeine, alcohol, aged cheeses, processed meats, and artificial sweeteners.
An elimination diet can help pinpoint specific food triggers.
5. Medication and alternative therapies
Preventive medications may be prescribed for frequent migraines.
Acupuncture and magnesium supplements can provide relief for some sufferers.
“Migraines are complex and vary widely from person to person. Understanding the different types, recognising their symptoms, and implementing lifestyle strategies can make a significant difference in managing them.
“If you or someone you know experiences frequent migraines, there is help available and consulting a doctor for an individualised treatment plan is recommended. Through awareness and prioritising self-care, quality of life can be greatly improved for those suffering from migraines,” Dr Huth concludes.
Female hormones can suppress pain by making immune cells near the spinal cord produce opioids, a new study from researchers at UC San Francisco has found. This stops pain signals before they get to the brain.
The discovery could help with developing new treatments for chronic pain. It may explain why some painkillers work better for women than men and why postmenopausal women, whose bodies produce less of the key hormones oestrogen and progesterone, experience more pain.
The work reveals an entirely new role for T regulatory immune cells (T-regs), which are known for their ability to reduce inflammation.
“The fact that there’s a sex-dependent influence on these cells – driven by oestrogen and progesterone – and that it’s not related at all to any immune function is very unusual,” said Elora Midavaine, PhD, a postdoctoral fellow and first author of the study, which appears in Science.
The researchers looked at T-regs in the protective layers that encase the brain and spinal cord in mice. Until now, scientists thought these tissue layers, called the meninges, only served to protect the central nervous system and eliminate waste. T-regs were only discovered there in recent years.
“What we are showing now is that the immune system actually uses the meninges to communicate with distant neurons that detect sensation on the skin,” said Sakeen Kashem, MD, PhD, an assistant professor of dermatology. “This is something we hadn’t known before.”
That communication begins when a neuron, often near the skin, receives a stimulus and sends a signal to the spinal cord.
The team found that the meninges surrounding the lower part of the spinal cord harbour an abundance of T-regs. To learn what their function was, the researchers knocked the cells out with a toxin.
The effect was striking: Without the T-regs, female mice became more sensitive to pain, while male mice did not. This sex-specific difference suggested that female mice rely more on T-regs to manage pain.
“It was both fascinating and puzzling,” said Kashem, who co-led the study with Allan Basbaum, PhD. “It actually made me sceptical initially.”
Further experiments revealed a relationship between T-regs and female hormones that no one had seen before: Estrogen and progesterone were prompting the cells to churn out enkephalin, a naturally occurring opioid.
Exactly how the hormones do this is a question the team hopes to answer in a future study. But even without that understanding, the awareness of this sex-dependent pathway is likely to lead to much-needed new approaches for treating pain.
In the short run, it may help physicians choose medications that could be more effective for a patient, depending on their sex. Certain migraine treatments, for example, are known to work better on women than men.
This could be particularly helpful for women who have gone through menopause and no longer produce oestrogen and progesterone, many of whom experience chronic pain.
The researchers have begun looking into the possibility of engineering T-regs to produce enkephalin on a constant basis in both men and women.
Patients prescribed medicinal cannabis in Australia maintained improvements in overall health-related quality of life (HRQL), fatigue, and sleep disturbance across a one-year period, according to a study published April 2, 2025, in the open-access journal PLOS One by Margaret-Ann Tait from The University of Sydney, Australia, and colleagues. Anxiety, depression, insomnia, and pain also improved over time for those with corresponding health conditions.
Research into the therapeutic benefits of medicinal cannabis has increased since the discovery of the analgesic properties in cannabis plant compounds. In 2016, advocacy groups lobbied the Australian government to bring about legislation changes that allow patients who were not responding to conventional treatment to access medicinal cannabis with a prescription from clinicians. More than one million new patients in Australia have received medicinal cannabis prescriptions for more than 200 health conditions.
A multicenter prospective study called the QUEST initiative (QUality of life Evaluation STudy) recruited adult patients with any chronic health condition newly prescribed medicinal cannabis oil between November 2020 and December 2021. Tait and colleagues gathered 12-month follow-up data to determine if previously reported improvements at three months would be maintained long-term. Of 2744 consenting participants who completed baseline assessments, 2353 also completed at least one follow-up questionnaire and were included in analyses, with completion rates declining to 778/2353 (38%) at 12 months. Participants with clinician-diagnosed conditions completed questionnaires covering condition-specific symptoms, and HRQL, which encompasses physical, emotional, social, and cognitive function, as well as bodily discomfort.
The researchers found that short-term improvements in overall HRQL reported at three months were maintained over a 12-month period in patients prescribed medicinal cannabis in Australia. People with chronic health conditions reported improvements in fatigue, pain, and sleep. Patients with anxiety, depression, insomnia, or chronic pain diagnoses also showed improvements in condition-specific symptoms over 12 months. Patients treated for generalized anxiety, chronic pain, insomnia, and PTSD all showed improvements in HRQL. Participants with movement disorders had improved HRQL but no significant improvements in upper extremity function scores.
The study was large enough to assess patients across a wide range of chronic conditions and socio-demographics in a real-world setting. However, without a control group, it was not possible to confidently attribute changes over time to medicinal cannabis.
Despite this limitation, the results suggest that prescribing medicinal cannabis to patients with chronic health conditions may improve pain, fatigue, insomnia, anxiety, and depression and overall HRQL. The findings also suggest that any improvements would be apparent quickly and maintained long-term. According to the authors, the results from this study contribute to the emerging evidence base to inform decision making both in clinical practice and at the policy level.
The authors add: “This is promising news for patients who are not responding to conventional medicines for these conditions.”
“It’s really sore,” my (Josh’s) five-year-old daughter said, cradling her broken arm in the emergency department.
“But on a scale of zero to ten, how do you rate your pain?” asked the nurse.
My daughter’s tear-streaked face creased with confusion.
“What does ten mean?”
“Ten is the worst pain you can imagine.” She looked even more puzzled.
As both a parent and a pain scientist, I witnessed firsthand how our seemingly simple, well-intentioned pain rating systems can fall flat.
What are pain scales for?
The most common scale has been around for 50 years. It asks people to rate their pain from zero (no pain) to ten (typically “the worst pain imaginable”).
This focuses on just one aspect of pain – its intensity – to try and rapidly understand the patient’s whole experience.
How much does it hurt? Is it getting worse? Is treatment making it better?
Rating scales can be useful for tracking pain intensity over time. If pain goes from eight to four, that probably means you’re feeling better – even if someone else’s four is different to yours.
But that common upper anchor in rating scales – “worst pain imaginable” – is a problem.
People usually refer to their previous experiences when rating pain. Photo by Rodnae Productions on Pexels
A narrow tool for a complex experience
Consider my daughter’s dilemma. How can anyone imagine the worst possible pain? Does everyone imagine the same thing? Research suggests they don’t. Even kids think very individually about that word “pain”.
People typically – and understandably – anchor their pain ratings to their own life experiences.
This creates dramatic variation. For example, a patient who has never had a serious injury may be more willing to give high ratings than one who has previously had severe burns.
“No pain” can also be problematic. A patient whose pain has receded but who remains uncomfortable may feel stuck: there’s no number on the zero-to-ten scale that can capture their physical experience.
In reality, pain ratings are influenced by how much pain interferes with a person’s daily activities, how upsetting they find it, their mood, fatigue and how it compares to their usual pain.
Other factors also play a role, including a patient’s age, sex, cultural and language background, literacy and numeracy skills and neurodivergence.
For example, if a clinician and patient speak different languages, there may be extra challenges communicating about pain and care.
Still, we work with the tools available. There is evidence people do use the zero-to-ten pain scale to try and communicate much more than only pain’s “intensity”.
So when a patient says “it’s eleven out of ten”, this “impossible” rating is likely communicating more than severity.
They may be wondering, “Does she believe me? What number will get me help?” A lot of information is crammed into that single number. This patient is most likely saying, “This is serious – please help me.”
In everyday life, we use a range of other communication strategies. We might grimace, groan, move less or differently, use richly descriptive words or metaphors.
Collecting and evaluating this kind of complex and subjective information about pain may not always be feasible, as it is hard to standardise.
As a result, many pain scientists continue to rely heavily on rating scales because they are simple, efficient and have been shown to be reliable and valid in relatively controlled situations.
But clinicians can also use this other, more subjective information to build a fuller picture of the person’s pain.
Visual scales are one tool. For example, the “Faces Pain Scale-Revised” asks patients to choose a facial expression to communicate their pain. This can be particularly useful for children or people who aren’t comfortable with numeracy and literacy, either at all, or in the language used in the health-care setting.
A vertical “visual analogue scale” asks the person to mark their pain on a vertical line, a bit like imagining “filling up” with pain.
Listen for the story behind the number, because the same number means different things to different people.
Use the rating as a launchpad for a more personalised conversation. Consider cultural and individual differences. Ask for descriptive words. Confirm your interpretation with the patient, to make sure you’re both on the same page.
Patients
To better describe pain, use the number scale, but add context.
Try describing the quality of your pain (burning? throbbing? stabbing?) and compare it to previous experiences.
Explain the impact the pain is having on you – both emotionally and how it affects your daily activities.
Paediatric health professionals are trained to use age-appropriate vocabulary, because children develop their understanding of numbers and pain differently as they grow.
A starting point
In reality, scales will never be perfect measures of pain. Let’s see them as conversation starters to help people communicate about a deeply personal experience.
That’s what my daughter did — she found her own way to describe her pain: “It feels like when I fell off the monkey bars, but in my arm instead of my knee, and it doesn’t get better when I stay still.”
From there, we moved towards effective pain treatment. Sometimes words work better than numbers.
This effect even occurs with virtual nature – such as nature videos
Photo by Sebastian Unrau on Unsplash
In a new study, an international team of neuroscientists led by the University of Vienna has shown that experiencing nature can alleviate acute physical pain. Surprisingly, simply watching nature videos was enough to relieve pain. Using functional magnetic resonance imaging, the researchers found that acute pain was rated as less intense and unpleasant when watching nature videos – along with a reduction in brain activity associated with pain. The results, published in Nature Communications, suggest that nature-based therapies can be used as promising complementary approaches to pain management.
“Pain processing is a complex phenomenon” explains study lead and doctoral student Max Steininger from the University of Vienna. In order to better understand it and identify treatment options, Steininger and his colleagues investigated how nature exposure influences pain: participants suffering from pain were shown three types of videos: a nature scene, an indoor scene, and an urban scene. The participants rated the pain while their brain activity was measured using functional magnetic resonance imaging. The results were clear: when viewing the nature scene, the participants not only reported less pain but also showed reduced activity in brain regions associated with pain processing.
By analyzing the brain data, the researchers showed that viewing nature reduced the raw sensory signal the brain receives when in pain. “Pain is like a puzzle, made up of different pieces that are processed differently in the brain. Some pieces of the puzzle relate to our emotional response to pain, such as how unpleasant we find it. Other pieces correspond to the physical signals underlying the painful experience, such as its location in the body and its intensity. Unlike placebos, which usually change our emotional response to pain, viewing nature changed how the brain processed early, raw sensory signals of pain. Thus, the effect appears to be less influenced by participants’ expectations, and more by changes in the underlying pain signals,” explains Steininger.
Claus Lamm, head of research in the group, adds: “From another ongoing study, we know that people consistently report feeling less pain when exposed to natural environments. However, the underlying reason for this has remained unclear – until now. Our study suggests that the brain reacts less to both the physical source and the intensity of the pain.”
The current study provides important information on how nature can help alleviate pain and highlights that nature-based therapeutic approaches can be a useful addition to pain treatment. The fact, that this effect was observed by simply watching nature videos suggests that taking a walk outdoors may not be necessary. Virtual nature – such as videos or virtual reality – appears to be effective as well. This opens up a wide range of possible applications in both the private and medical sectors, providing people with a simple and accessible way to relieve their pain.
The study was conducted at the University of Vienna in collaboration with researchers from the Universities of Exeter and Birmingham (UK) and the Max Planck Institute for Human Development.
Facial pain and discomfort related to the temporomandibular joint (TMJ) is the second-leading musculoskeletal disorder, after chronic back pain, affecting 8% to 12% of Americans. Current treatments for TMJ disorders are not always sufficient, leading researchers to further explore the vast nerve and vessel network connected to this joint – the second largest in the human body.
In a study published in December 2024 in the journal Pain, a research team led by Yu Shin Kim, PhD, associate professor at the The University of Health Science Center at San Antonio (UT Health San Antonio), observed for the first time the simultaneous activity of more than 3000 trigeminal ganglion (TG) neurons, which are cells clustered at the base of the brain that transmit information about sensations to the face, mouth and head.
“With our novel imaging technique and tools, we can see each individual neuron’s activity, pattern and dynamics as well as 3000 neuronal populational ensemble, network pattern and activities in real time while we are giving different stimuli,” said Kim.
When the TMJ is injured or misaligned, it sends out signals to increase inflammation to protect the joint. However, this signaling can lead to long-term inflammation of the joint and other parts of the highly connected nerve network, leading to chronic pain and discomfort. About 80% to 90% of TMJ disorders occur in women, and most cases develop between the ages of 15–50.
Activation at the cellular level
Previous animal studies observed behavioural changes related to pain, but this study was the first to record reactions at the cellular level and their activities. To see which portions of the nerve pathway respond to various types of pain, Kim’s team created different models of pain and observed the neuronal activity with high-resolution confocal imaging, which uses a high-resolution camera and scanning system to observe neurons in action.
The team discovered that during TMJ activation, more than 100 neurons spontaneously fire at the same time. Activation was observed in localised areas of the TMJ innervated to TG neurons. The localisation of this activation highlights the specific neural pathways involved in TMJ pain, offering deeper insight into how pain develops and spreads to nearby areas. The study is also the first to quantify the degree of TG neuronal sensitivity and network activities.
Potential link to migraine, headaches
Chronic TMJ pain in humans is often linked to other pain comorbidity such as migraines and other headaches. Kim’s team observed this crossover in the in vivo model as inflammation of TG neurons spread to the nearby orofacial areas. Kim’s previous research demonstrated how stress-related migraine pain originates from a certain molecule, begins in the dura and innervates throughout the dura and TG neurons. This current study and novel imaging technique further reveals potential connections between the TMJ, migraines and other headaches.
Potential of CGRP treatment
Calcitonin gene-related peptides (CGRP), molecules involved in transmitting pain signals and regulating inflammation, are often found in higher amounts in synovial fluid of TMJ disorder patients. Synovial fluid surrounds joints in the body, helping to reduce friction between bones and cartilage. Higher amounts of CGRP are often associated with increased pain and inflammation. Kim hypothesised in this study that a reduction in CGRP may reduce TMJ disorder symptoms. He found that CGRP antagonist added to the synovial fluid relieved both TMJ pain and hypersensitivity of TG neurons.
Currently, there are no Federal Drug Administration-approved medications for TMJ disorders other than non-steroidal anti-inflammatory drugs (NSAIDS). While some CGRP antagonist medications are FDA-approved for treating migraines, this study suggests these drugs may also provide relief for TMJ disorders. Confirmation of the positive effect of the drug on TMJ pain is a major leap forward in understanding how CGRP affect TMJ pain, said Kim.
“This imaging technique and tool allows us to see pain at its source – down to the activity of individual neurons – offering unprecedented insights into how pain develops and spreads. Our hope is that this approach will not only advance treatments for TMJ disorders but also pave the way for understanding and managing various chronic pain conditions more effectively,” said Kim.
Researchers at WashU Medicine and Stanford University developed a compound that relieves pain in mice but doesn’t affect the brain, thereby avoiding mind-altering side effects and abuse potential. The custom-designed molecule, derived from cannabis, may provide an alternative to opioids for treating chronic pain. The compound is illustrated here in cyan, nestled within a protein (green and purple) involved in sensing pain. Credit: Tasnia Tarana
In the quest to develop a safe, effective alternative to opioids, researchers have developed a compound that mimics a natural molecule found in the cannabis plant, harnessing its pain-relieving properties without causing addiction or mind-altering side effects in mice.
While more studies are needed, the compound shows promise as a nonaddictive pain reliever. The study, from Washington University School of Medicine in St. Louis and Stanford University, appears in Nature.
“There is an urgent need to develop nonaddictive treatments for chronic pain, and that’s been a major focus of my lab for the past 15 years,” said the study’s senior author Susruta Majumdar, PhD, a professor of anaesthesiology at WashU Medicine. “The custom-designed compound we created attaches to pain-reducing receptors in the body but by design, it can’t reach the brain. This means the compound avoids psychoactive side effects such as mood changes and isn’t addictive because it doesn’t act on the brain’s reward centre.”
Opioids dull the sensation of pain in the brain and hijack the brain’s reward system, triggering the release of dopamine and feelings of pleasure, which make the drugs so addictive. Despite widespread public health warnings and media attention focused on the dangers of opioid addiction, numerous overdose deaths still occur. In 2022, some 82 000 deaths in the U.S. were linked to opioids.
“For millennia, people have turned to marijuana as a treatment for pain,” explained co-corresponding author Robert W. Gereau, PhD, professor of anaesthesiology and director of the WashU Medicine Pain Center. “Clinical trials also have evaluated whether cannabis provides long-term pain relief. But inevitably the psychoactive side effects of cannabis have been problematic, preventing cannabis from being considered as a viable treatment option for pain. However, we were able to overcome that issue.”
The mind-altering properties of marijuana stem from natural molecules found in the cannabis plant referred to as cannabinoid molecules. They bind to a receptor, called cannabinoid receptor one (CB1), on the surface of brain cells and on pain-sensing nerve cells throughout the body.
Working with collaborators at Stanford University, co-first author Vipin Rangari, PhD, a WashU Medicine postdoctoral research associate in Majumdar’s laboratory, designed a cannabinoid molecule with a positive charge, preventing it from crossing the blood-brain barrier into the brain while allowing the molecule to engage CB1 receptors elsewhere in the body. By modifying the molecule such that it only binds to pain-sensing nerve cells outside of the brain, the researchers achieved pain relief without mind-altering side effects.
They tested the modified synthetic cannabinoid compound in mouse models of nerve-injury pain and migraine headaches, measuring hypersensitivity to touch as a proxy for pain. Applying a normally non-painful stimulus allows researchers to indirectly assess pain in mice. In both mouse models, injections of the modified compound eliminated touch hypersensitivity.
For many pain relievers, particularly opioids, tolerance to the medications over time can limit their long-term effectiveness and require higher doses of medication to achieve the same level of pain relief. In this study, the modified compound offered prolonged pain relief – the animals showed no signs of developing tolerance despite twice-daily treatments with the compound over the course of nine days. This is a promising sign that the molecule could be used as a nonaddictive drug for relief of chronic pain, which requires continued treatment over time.
Eliminating the compound’s tolerance resulted from the bespoke design of the compound. The Stanford collaborators performed sophisticated computational modeling that revealed a hidden pocket on the CB1 receptor that could serve as an additional binding site. The hidden pocket, confirmed by structural models, leads to reduced cellular activity related to developing tolerance compared to the conventional binding site, but it had been considered inaccessible to cannabinoids. The researchers found that the pocket opens for short periods of time, allowing the modified cannabinoid compound to bind, thus minimizing tolerance.
Designing molecules that relieve pain with minimal side effects is challenging to accomplish, said Majumdar. The researchers plan to further develop the compound into an oral drug that could be evaluated in clinical trials.
