The PRF Virtual Correspondents Blog – Cycle 3
Posted April 14, 2021 | Correspondents' Programs News
Thirteen early-career pain researchers and clinicians are taking part in the third cycle of the PRF Virtual Correspondents Program. This science communications training program provides participants with knowledge and skills needed to communicate science effectively to a wide range of pain researchers, and to patients and the broader public. Throughout the course of the program, the Correspondents will conduct interviews and podcasts with leading pain researchers, provide news and virtual meeting coverage – and blog posts! Take a look at their posts below, which will be published weekly over the next six weeks.
Meet the PRF Correspondents
Week 6: Wednesday, April 14, 2021
A Multidisciplinary and Holistic Approach to Pain Management
Pain: Not Only a Neuronal Affair
Words Matter When Talking About Pain
Words Matter When Prescribing Exercises
Tweets Containing #pain or #migraine: What Do People Write About?
Working With, Instead of Fighting Against, the Chronic Pain Monster
Cold Pain in the Teeth Reimagined: A Key Role for TRPC5 in Odontoblasts
The Link Between Fibromyalgia, Women, and Autoimmunity
Precision Medicine: Diagnosing and Treating Central Sensitization
Remember Anne of Green Gables? That’s the name I would give to one of the mice in this study if I were the author. In this recent investigation, red-haired mice (wait, what?) are used to explore the mechanism that underlies the low sensitivity to acute painful stimuli observed in redheads.
But let’s take a step back first: What causes red hair? Genetic variants in the melanocortin 1 receptor (MC1R) expressed on melanocytes – the pigment-producing cells of the skin – are responsible for red hair. MC1R is a G protein-coupled receptor that, once activated by melanocyte-stimulating hormone (MSH), leads to the production of the brown/black pigment eumelanin. In people with loss-of-function variants, to which MSH cannot bind, the pigment pheomelanin (yellow/red) is produced instead. It should be noted that aside from MC1R, other genes contribute to red hair, and variants in MC1R are often also observed in blonde individuals.
The question arises whether loss-of-function alterations in MC1R are also responsible for changes in pain sensitivity. In a cohort of 17 redheads (just imagine an Irish football team) it was found that higher pain thresholds were associated with regulatory variants (mutations in untranslated regions), rather than missense mutations. From the prevalence of different variants in previous studies and their own, the authors estimated that about half of redheads will have a “pain-protective” phenotype.
Back to our mouse Anne. The researchers wanted to understand the mechanism that mediates these high pain thresholds observed in red-haired individuals. To do so, they used a mouse strain with a defective MC1R, to recapitulate the human loss-of-function variants. These mice showed increased pain thresholds to thermal and mechanical stimuli, as previously reported. This effect of MC1R was determined by its expression in melanocytes, but independent from pigment production.
The red-haired mice were secreting lower levels of proopiomelanocortin, a precursor molecule of MSH and the endogenous opioid β-endorphin. While the latter is antinociceptive through activation of opioid receptors, MSH is pronociceptive. In line with this, administration of an MSH-mimicking peptide to red-haired mice matched their pain thresholds to those of black mice. This pointed the authors towards a melanocortin receptor other than MC1R as responsible for MSH actions. Using knockout mice, MC4R was identified as such.
Finally, based on co-localization experiments, the authors propose that MC4R antagonizes opioid receptors (see illustration below). Therefore, in red-haired mice, the low levels of MSH result in reduced antagonism of opioid receptors and ultimately low pain sensitivity. The flipside to this pain resistance is the sensitivity to ultraviolet (UV) rays and skin cancer risk. Which one would you prefer if you could choose?
Larissa de Clauser, PhD from University College London, now based in Italy.
Before delving into my final post, I would like to say a massive thank you to PRF and RELIEF for the opportunity to participate in this program, and to you, the PRF community, for your engagement with the blog. I had a great time writing these posts and I hope you have enjoyed reading them!
Last year I woke up in the middle of the night to a relentless pain emanating from my right big toe. It was so bad that even the weight of the sheet was unbearable. Looking down I saw that my toe was red, swollen and hot to the touch. Had I stubbed it? Had I dropped something on it? Well, no, unfortunately I knew it was likely something else because, from what I could see, it looked quite a lot like gout.
Not a great realization, I have to admit. Most people, including myself, associate gout – a form of inflammatory arthritis – with somewhat of an excessive lifestyle; this is something that has not been helped by its previous and ill-advised nickname, the “disease of kings. ”As someone who is relatively young and healthy (plus a pescatarian and a woman!), I couldn’t quite understand why I would suddenly develop it.
Of course, the first thing I did was go online to do some research and while doing so I realized that gout could in fact be a possibility. You see, my father has fallen victim to its attacks for many decades, and with gout having a high level of heritability, he may seemingly have passed on the joys of this fate to me (thanks Dad!). Alongside the finding that the typical Western diet is associated with a 42% increased risk of developing gout, I suppose it is less surprising a prospect than I had previously thought.
Gout is a systemic disease, occurring when hyperuricemia – a sustained increase in serum urate levels resulting in oversaturation of urate in body tissue – leads to the formation and deposition of monosodium urate crystals in and around the joints. These crystals initiate inflammatory processes by being engulfed by macrophages, the body’s phagocytic immune cells, which in turn leads to the release of pro-inflammatory cytokines. Recurrent gout can cause major disability via chronic inflammation and joint degradation, with sufferers’ main outward symptom being pain. Luckily though, there is a definitive curative treatment for gout via therapies that lower urate levels.
Through reading I discovered that gout is actually the most common form of inflammatory arthritis globally, with a high prevalence in developed countries along with a worrying rise in case numbers. It is more prevalent in men than women, and in the older population, and has an array of predisposing risk factors including obesity and diabetes, along with the previously mentioned genetic susceptibility. A major contributor to gout is of course diet, with consumptions of purine-rich foods, such as red meat and seafood, leading to increased uric acid precursors and gout onset.
Unsurprisingly, as a long-term sufferer my father is well versed in what to avoid food-wise, so while I was on the phone telling him of my recent misfortune, he provided some advice: "Definitely avoid hoppy beer. And be careful of red wine. Oh, and pulses…. Seafood can also do it." Not ideal, as he was essentially listing the foodstuffs I enjoy.
Thankfully, the symptoms of my attack diminished within a day. Without an opportunity for a diagnosis at that time I am still reluctant to admit that it was actually gout. Only the next flare will tell, and in the meantime, no beer nor lentil dhals for me!
Oakley Morgan, PhD student, University College London, UK.
A Multidisciplinary and Holistic Approach to Pain Management
“Not only is it important to ask questions and find the answers, as a scientist I felt obligated to communicate with the world what we were learning.” – Stephen Hawking
The PRF Correspondents Program epitomizes leadership in providing the tools for effective science communication. Being a part of this program has allowed me to engage with the broader PRF and IASP community while also providing an opportunity to communicate my research.
I had anticipated that this program would help me refine my writing skills but what I did not factor in was the cathartic process of writing itself. With every blog I re-visited memories of my medical and research training, the amazing people I have met along the way, and the plethora of experiences I've had.
I explored five constructs in my blog posts: the power of social support and relationships; dyadic coping (intimate partner-provided support); moving from treating pain to caring for the patient; overcoming language barriers in order to provide equal healthcare opportunities for all; and our collective role in meeting the challenge of healthcare disparities.
I chose to write about these specific themes because they illustrate the need for a multidisciplinary and holistic approach to pain management; the impact of pain on almost all facets of life, including physical health, sleep, mental health, relationships, social life and employment makes this approach the best path forward. It will help improve pain disability, insomnia, and psychological distress in our patients while helping them reconnect with activities that bring joy and meaning to their life.
I am enjoying every minute of this program and I want to especially thank our PRF editor, Neil Andrews, for his encouragement and unwavering support. I also applaud my fellow Correspondents for sharing their own stories and making this process fun and exciting.
Finally, I want to thank you, our readers, for your encouragement, comments and thoughts. It’s been an absolute pleasure.
I am continuing my efforts to communicate science with an exciting upcoming podcast with Professor Judith Turner. Stay tuned…
Follow me on Twitter @DrManasiMurthy
Manasi M. Mittinty, MD, PhD, lecturer, University of Sydney, Australia.
Pain: Not Only a Neuronal Affair
When we think about pain, whether as a scientist, clinician or patient, there is a general understanding that it is a neurobiological response involving the brain and neurons. As researchers we understand that there is detection of noxious stimuli by nociceptors, processing in the brain and movement responses. However, pain does not rely entirely on neurons; other cells are also involved. In particular, immune cells are involved at multiple stages of pain processing, including in the spinal cord, and these cells generally release inflammatory mediators to enhance nociceptive signaling.
In the skin, the ends of nociceptive neurons have historically been described as “free.” That is, they extend out almost like branches of a tree with no leaves, detecting noxious stimuli. This was always noteworthy as the neurons in the skin responsible for other sensations like touch, vibration and pressure have specialized organs surrounding them that help to transmit the signal from the skin to the neurons – more like branches of a tree that have fruit on the end. Nociceptive neurons were described as free as they did not have a specialized structure that served a similar purpose.
However, recent work has indicated that there are nociceptive neurons whose endings are not free and are surrounded by a mesh of non-neuronal cells that interact with the neurons. These cells were dubbed nociceptive Schwann cells. The research group behind this work, led by Patrik Ernfors, used light to determine whether the network of Schwann cells has any effect on pain. The technique is called optogenetics and involves genetically inserting a light-sensitive protein into neurons in order to activate or turn off the cells upon light exposure. When the light was turned on and aimed at the paw of mice to activate only the Schwann cells, the mice flinched and retracted their paws as if they were in pain. This suggested that the Schwann cells do interact with neurons and are involved in nociceptive signaling.
The question remained as to whether these cells are involved in all types of pain or a specific type. To answer this, the group used optogenetics and saw that the cells were inherently and primarily mechanosensitive, though there was some involvement with cold and heat pain. This is particularly interesting as our understanding of the way that neurons detect mechanical pain has been quite elusive, perhaps in part because the neurons require help from other sources.
For researchers interested in this debate, could this provide more evidence for polymodal nociceptors (nociceptive neurons that respond to a variety of noxious stimuli)? Perhaps neurons that respond to hot or cold can also respond to mechanical pain with the help of the mechanically-sensitive Schwann cells. It is a possible avenue of further study.
Excitingly, not only can non-neuronal cells also detect mechanical stimuli and transmit that to neurons, but it may eventually be time to change the textbooks about the long-held view of nociceptive neurons as having free nerve endings in the skin.
Frederick Jones, CASE PhD student, University of Leeds, UK, and Eli Lilly & Co, US.
Words Matter When Talking About Pain
Words are important. The language we use and the advice and guidance we share has great significance to a person living with pain. The words we use may carry a sense of hope and possibility or be associated with pessimism and low expectations. In fact, the words used in clinical conversations and in writing can influence a person’s mood, self-esteem, feelings of happiness or depression, understanding of their problem, and can even influence pain itself.
A growing body of research has shown that the words clinicians use to describe a health condition can also influence a person’s decisions about treatment. For example, words that elicit strong negative reactions may make you more likely to choose surgical treatment even when equally effective and safer treatment options are available.
A recent study found that the clinician’s use of certain medical words might be encouraging people with shoulder pain to say “yes” to unnecessary shoulder surgery. This randomized controlled trial investigated the use of six diagnostic labels for a common type of shoulder pain. Participants were presented with six hypothetical scenarios with the only difference between scenarios being the words used to describe the person’s shoulder pain. People told they had a “rotator cuff tear” wanted surgery the most whereas people told they had “bursitis” (inflammation of a fluid-filled sac in the shoulder) wanted surgery the least.
Given how important words can be to a person in pain, it is imperative that clinicians consider whether the words they use to describe a condition might be causing unnecessary fear or concern. Changing the words we use and the stories we tell to describe painful conditions is a simple strategy that could improve the lives of people living with pain.
Aidan G. Cashin, PhD Candidate, Neuroscience Research Australia (NeuRA); University of New South Wales.
Words Matter When Prescribing Exercises
Exercise is a core component of the management of chronic pain conditions. Many different types of exercise help reduce pain and disability, and have general positive effects on cardiovascular health, mental health and sleep, among others.
One of the many reasons why exercise is beneficial for pain is the exercise-induced hypoalgesia phenomenon. Studies have shown that even a single session of exercise can have a positive effect on pain sensitivity and pain tolerance. This means that doing aerobic or resistance exercise directly reduces pain, like taking a pill. While this phenomenon is very consistent in pain-free individuals, the positive effects are not as strong in people with chronic pain.
A recent study investigated if information given before exercise can influence the hypoalgesia effect of exercise. Researchers randomized people into positive (“studies have shown that exercise reduce pain”), neutral (only information about how to perform the exercise) and negative (“studies have shown that exercise can induce pain”) pre-exercise information groups. The study revealed that, while the positive and neutral information groups showed a hypoalgesia effect with exercise, the negative information group showed the opposite – an increase in pain sensitivity (hyperalgesia effect).
How do these results relate to the prescription of exercise for people with pain? Many studies have shown that explanations from health professionals may have a strong biomechanical orientation. For instance, frequent advice for low back pain is that people should be active, but they should also be careful to not injure their back. They receive encouragement to exercise but at the same time they are told to control their posture, to activate their deep muscles, to move in the “right” way or to be careful not to do too much. This conflicting advice may increase the perceived threat of exercise and have a negative effect with regard to exercise-induced hypoalgesia. Additionally, it can also negatively impact self-efficacy and result in kinesiophobia or unhelpful beliefs.
Therefore, to enhance the positive effect of exercise in people with chronic pain, clinicians should promote positive messages about the effect of exercise. They should also discuss potential unhelpful beliefs about doing exercise, and promote self-efficacy and confidence.
Words matter – and probably even more than the type of exercise, when it comes to pain.
Guillaume Christe, PhD student, Haute École de Santé Vaud (HESAV), Switzerland.
Tweets Containing #pain or #migraine: What Do People Write About?
Many people these days spend countless of hours on social media writing about everything between heaven and earth. As a health and medical scientist involved in pain research, I am interested in what people write about pain and migraine and how they do it. Therefore, I decided to conduct a preliminary sentiment analysis of Twitter content to find out. Sentiment has been described as “a metric commonly used to investigate the positive or negative opinion” within tweets. So it can tell us something about the tone of tweets.
Unsurprisingly, negative sentiments are used more often in tweets containing #pain or #migraine than positive sentiments are. So, what negative sentiments are most commonly used? I looked into the top 20 negative sentiments in tweets posted between April 2 to April 9, 2021. There were 11 negative sentiments that the tweets containing #pain or #migraine had in common. Of these sentiments, four caught my attention: stress, anxiety, depression, and inflammation. I decided to further dissect those using information from the literature.
The sentiment analysis was conducted using Twitter content available through the Twitter API and is therefore subject to the terms and conditions put forward by Twitter. Credit: The R package rtweet by Kearney MW (2019) was used for collecting tweets and carrying out the sentiment analysis. Thanks to Vajiha Sipra for inspiration.
Stress
The link between stress and pain is well-known. However, which comes first depends on the situation. We know that pain can cause stress and that stress can cause pain. Stress is also known to be a trigger of migraine attacks and is widely recognized as an important factor in disease.
Anxiety and depression
Anxiety and chronic pain tend to co-occur (see here and here). Interestingly, anxiety is a larger contributor to the risk of developing migraine than depression. Nevertheless, headache frequency tends to increase if patients are experiencing both anxiety and depression. There also seems to be a connection between the severity of anxiety and living with migraine.
Inflammation
In the central nervous system, altered proinflammatory molecule profiles have been observed in the context of chronic pain, with increased pain sensitivity and pain arising from a stimulus that would not normally be considered painful. Controlling inflammation in the nervous system has been suggested as a way to treat chronic pain.
Even though the tweets are full of negative sentiments, words like “relief,” “recovery” and “support” are also used. So there might be light at the end of the tunnel for some of those living with pain. As I wrote in my first blog post, there are likely more than a billion people in pain worldwide (about 1 in 5 people). Therefore, even slight progress in the development of novel treatment strategies is worth celebrating. As it has sometimes been said, “a little progress each day adds up to big results.”
Simona Denise Frederiksen, postdoctoral associate, University of Calgary, Canada.
Working With, Instead of Fighting Against, the Chronic Pain Monster
Throughout my posts during my time here as a PRF Virtual Correspondent, I have been open and direct in talking about my battles with the chronic pain monster (see “Too Young” to Be in This Much Pain, Fighting the Chronic Pain Dragon, and Living With the Chronic Pain Monster).
Well, today my pain monster is rearing its ugly head. It does not care that I have deadlines to meet and things to do. When I try ignoring it, it sinks its teeth deeper into me, demanding to be acknowledged.
I have also openly discussed my own use of prescription opioids as part of my toolkit in fighting the pain monster (see A Researcher, a Pain Patient, and an Artist and Understanding the Failure of Translation in the Pain Field). But this is such an important topic, so I feel the need to dig a little deeper into it.
In the past, I too felt shame in utilizing opioids as part of my pain management regimen. When needing to take my dose in public, I would worry about making sure no one would see me, as if I were inherently doing something wrong in taking medicine that allowed me to carry on with my day.
I refuse to feel ashamed of using a medication, especially when all others have failed and better options are currently unavailable. If it were not for my opioids helping me tame the pain monster today, I would not be able to stare at the bright computer screen long enough to write or push past the throbbing, spontaneous burning and stabbing sensations felt throughout my entire body. Before I took my medication, I was nearly unable to move my neck, and I could not close my hands all the way. I felt like the tinman from The Wizard of Oz – simply substitute the oil needed for stiffness with my pain cream.
Just thirty minutes ago I was on the verge of tears because I physically could not function at high enough levels to be productive. I had to be in complete darkness and silence, so that meant not being able to use a phone or look at my computer screen (sensory sensitivities are a common occurrence in migraine sufferers.)
All day today I have been trying to type this post. But, for the last four days, I have been dealing with fluctuating between a minor headache and a throbbing migraine accompanied by a full-body pain flare-up. I carved out time in my schedule specifically to write this post, so I grew increasingly frustrated with myself as the clock ticked by while the page remained empty.
I felt as if I was letting myself and others down. I wanted so badly to work, but my body was just not having it. I put so much pressure on myself to always be this eloquent weaver of words, to prove to the world that despite my pain I can do all the things and more that “everyone else” can do. I think a lot of chronic illness patients, whether they live with mental or physical disabilities, know this internal turmoil all too well. We do not want to seem lazy, or unaccountable, but the unpredictable nature of the chronic pain monster means we cannot always plan accordingly.
As the hours kept passing by, I began to realize the irony in my situation: My chronic pain was preventing me from writing a blog post about chronic pain. The brain fog, another common experience for chronic pain patients, made it difficult to think, so piecing together a cohesive post felt near impossible to do. Interestingly, the phenomenon of brain fog has also been noted in COVID-19 patients, both during their illness and in the months following recovery.
While jotting down my scattered thoughts and emotions accompanying my pain in real-time, I realized my post had practically written itself. In using my own lived experience as the building blocks for my writing, I decided that today, I am going to work with my chronic pain monster instead of solely fight against it.
Sarah D'Angelo, undergraduate student, Rutgers University, US.
Article Contributors:
