New animal studies in 2023 enhanced knowledge of the pathophysiological mechanisms underlying headache disorders, again showing the value of fundamental research for the field.
When Migraine Science Collaborative launched its new website in September of 2022, one feature we were – and still are – particularly excited about is our biweekly literature recap.
Every two weeks, MSC publishes a curated compilation of the most interesting and relevant new papers – about migraine, headache, and related fields, such as pain research – appearing in the scientific and medical literature. Our goal is to keep busy researchers and clinicians up to date on the latest findings with an easy-to-digest list of studies, saving them the time it takes to sort through the literature themselves.
The recap includes not only clinical and translational papers, but basic science papers, too. Fundamental research is important not only to advance understanding of disease mechanisms but also to identify potential drug targets, test novel medications against those targets, and generate new hypotheses that can be tested in translational and clinical studies. Ideas first explored in clinical research can also be back translated to the lab for further investigation.
Considering that one of MSC’s chief aims is to provide readers with knowledge of the basic science cutting edge – not only with our biweekly literature recap but also with our news coverage of the latest discoveries – this article highlights some of the best papers in basic science published in 2023, as the year comes to a close.
While the number of labs pursuing basic science research in our field is smaller compared to adjacent areas like pain, the past year proves that migraine and headache researchers continue to generate important findings, published in excellent journals, that are moving the field ahead. Here is a selection from among the most noteworthy basic science from 2023, with a focus on editor’s pick papers that also merited MSC news coverage.
Just say NO
Research from Greg Dussor and colleagues at the University of Texas at Dallas, US, took aim at nitric oxide (NO) signaling, hoping to learn more about how aberrant NO signaling plays its well-known role in migraine. The researchers discovered a key role for peroxynitrite, by showing that inhibition of this molecule, which sits in the NO pathway, decreased periorbital sensitivity, among other changes, in a mouse model of migraine. In addition, the research pointed to effects on mitochondria as a mechanism by which peroxynitrite exerts its influence, though, interestingly, only in male animals.
In our news story on the paper, Jon Borkum, a pain and headache expert at Health Psych Maine, Waterville, US, and the University of Maine, Orono, US, but who was not involved with the new research, said: “I think this is a beautiful piece of experimental research. I loved the precision of the methods and the precision of the thinking, so certainly this research will advance the field.”
The news story also covered a related clinical paper, thus showing how basic science and human research can converge to tell a powerful narrative about an important signaling pathway in migraine.
Learning more about cortical spreading depression
The phenomenon of cortical spreading depression (CSD), thought to underlie migraine aura, is of course well known to migraine researchers. A study published in July, from Dan Levy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US, and colleagues, pinpointed a new mechanism by which CSD affects afferent nociceptive neurons in the meninges. Using a rat model of CSD, the investigators identified a receptor called P2X7, which plays a role in ATP signaling, as a key player in the sensitization, but not the ongoing activation, of those neurons.
Our news story on this research cited Andrew Strassman, a pain and headache researcher also at Beth Israel and Harvard but who was not involved with the study, who told MSC: “This study provides another key piece to the puzzle of how the brain event, cortical spreading depression, that underlies the migraine aura acts on the sensory neurons in the meninges that are thought to initiate the migraine headache.”
Opioid-induced hyperalgesia and medication overuse headache
Despite their well-documented problems of addiction and abuse, opioids are still used to treat headache and pain. These drugs can also make headache worse, especially in people who already have a headache disorder – what’s known as medication overuse headache (MOH).
A study from Amynah Pradhan, Washington University School of Medicine in St. Louis, US, added new knowledge to the understanding of MOH, by using nitroglycerine and CSD mouse models of migraine to identify a signaling pathway contributing to MOH. Specifically, she and her colleagues found that inhibiting signaling between the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1, eased headache made worse by morphine overuse.
In our news coverage of the paper, our independent source, Andy Russo, University of Iowa, Iowa City, US, said this of the main result: “This is an exciting finding that reports a mechanistic link between opiates and migraine triggers. In Europe, MOH is not a problem since guidelines are clear that opioids should not be used, but it continues to be a problem in America. This study is a good first step to work around the problem.”
Previously, in a separate interview published at the beginning of 2023, we had asked Russo about his career and research. This is what he said when we asked him why animal models are important to advance knowledge about migraine:
“That’s an important question. Translatability of mouse studies has a poor track record, especially in the pain field. To avoid this, we build our studies based on human clinical data, and then dive into mechanisms in animals. Modeling migraine in animals has advanced the field significantly by telling us how CGRP is causing migraine. We have sophisticated tools to engineer mice in order to answer questions that are in no way possible [to address] in humans, especially in fields like epigenetics.”
Russo also emphasized in his interview the need for basic science researchers and clinicians to work together.
“I agree that there needs to be more crosstalk between researchers and clinicians. As a basic science researcher, I feel it’s important that clinicians keep us grounded; it’s really easy to get sidetracked by interesting nuggets of data, but clinicians need to ground our knowledge in what actually happens to patients. One important clinical aspect of migraine we need to look at more carefully in basic research is variability among patients – why do symptoms differ among different people, and how can we use mouse models to understand this?” Russo said.
A neuroimmune pathway
Research from Yu-Qing Cao, Washington University School of Medicine in St. Louis, US, and colleagues added to evidence that signaling between the nervous system and the immune system contributes to headache. Using mouse models of migraine, the group found that an immune system protein called CCL2 activates its receptor, CCR2, on macrophages and T cells, which increases CGRP signaling in trigeminal ganglion neurons. Inhibiting this signaling pathway reversed headache pain in the animal models.
In our news story reporting on the results, Michael Moskowitz, Massachusetts General Hospital and Harvard Medical School, Boston, US, who was not part of the research, said:
“This paper is important because it introduces a new therapeutic target for migraine, but also one that is consistent with the framework used to develop new drugs in the migraine field. This paper also underscores the importance of inflammation in migraine because of the identification of the macrophages as a target.”
Caffeine, behavior, and blood flow
A mouse study from UCLA researchers Kimiya Aframian, Dmitri Yousef Yengej, Guido Faas, Andrew Charles, and colleagues looked at how chronic caffeine affects wakefulness, sleep, and brain blood flow. Using their innovative, minimally invasive microchip/video system, the investigators discovered complex effects of caffeine on all of those parameters, including the paradox of increased brain blood flow during sleep, and decreased brain blood flow during awakeness.
The strength of the study, said outside expert Tom de Boer, Leiden University Medical Center, the Netherlands, in our news story covering the paper, was its use of chronic caffeine administration.
“It recently became clear that the effect of chronic caffeine on sleep is different compared to the effect of acute caffeine. It is well known that acute caffeine disturbs sleep and increases waking. But these are results obtained in humans who had to abstain from using caffeine for one or maybe two weeks, and in animals that were naïve to caffeine. However, nobody drinks coffee once every one to two weeks. Most of us use caffeine multiple times per day on a daily basis,” according to de Boer.
More editor’s picks
Take a look at these additional editor’s picks from the basic science literature in 2023 – and stay tuned for more MSC coverage of animal studies in 2024 and beyond…
- Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury
- Xenobiotic exposure and migraine-associated signaling: A multimethod experimental study exploring cellular assays in combination with ex vivo and in vivo mouse models
- Increased presynaptic excitability in a migraine with aura mutation
- PACAP38-related modulation of the cranial parasympathetic projection: a novel mechanism and therapeutic target in severe primary headache
- Aryl hydrocarbon receptors improve migraine-like pain behaviors in rats through the regulation of regulatory T cell/T-helper 17 cell-related homeostasis
- Inhibition of persistent sodium current reduces spreading depression-evoked allodynia in a mouse model of migraine with aura
- Effect of voluntary exercise on endogenous pain control systems and post-traumatic headache in mice
- PAR2 activation in the dura causes acute behavioral responses and priming to glyceryl trinitrate in a mouse migraine model
- Neuronal NLRP3 inflammasome mediates spreading depolarization-evoked trigeminovascular activation
The full archive of basic science papers that made it into the MSC literature recap in 2023 is available here.
Image credit: 123RF Stock Photo.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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