Kazan Federal University scientists find new mechanisms of predisposition to migraine

Scientists at Kazan Federal University, in a new study published in the journal International Journal of Molecular Sciences, demonstrated how systemic inflammation in the body can act as a powerful amplifier of migraine – attacks of throbbing headache often accompanied by sensitivity to noise and light. The work reveals molecular and cellular mechanisms linking the immune response with hyperactivation of the nervous system, opening prospects for the development of new therapeutic strategies.

Migraine is not just a headache, but a complex neurological disorder that significantly reduces people's quality of life. Despite progress in treatment, a full understanding of its pathogenesis remains one of the key challenges in neuroscience. For a long time, research focused on vascular and neurogenic theories. In recent years, however, more and more evidence has emerged for the involvement of neuroimmune interactions and inflammatory processes in the brain's membranes (the meninges) in triggering and sustaining a migraine attack.

In animal experiments, researchers from the Institute of Fundamental Medicine and Biology of KFU modeled a systemic inflammatory response by injecting bacterial lipopolysaccharide (LPS) – a component of the bacterial cell wall and a powerful trigger of immune activation. Special attention was paid to a model in which inflammation was initiated at early stages of organism development, making it possible to assess the long-term consequences of such exposure on the formation of pain sensitivity.

They found that systemic inflammation leads to enhanced degranulation of mast cells in the meninges. Mast cells are systems that, in response to a threat, release a complex of biologically active substances, including histamine, cytokines, and, importantly, serotonin. Serotonin is considered one of the key neurotransmitters involved in migraine pathogenesis. Under inflammatory conditions, the sensitivity of peripheral pain fibers of the trigeminal nerve to serotonin rises sharply.

"In our work, using a rat migraine model, inflammation made the pain system more irritable. Put simply, the nerve endings that trigger migraine pain responded more strongly and were activated more easily under the same triggers/stimuli. This manifested as more pronounced pain sensitivity to mechanical stimuli (allodynia), which normally do not cause pain, and photophobia. Therefore, it is more accurate to speak not about a transition from 'moderate to unbearable pain,' but about the fact that inflammation increases the likelihood of more intense symptoms and lowers the threshold for their appearance. This cannot be directly translated into human sensations scored in points, but the meaning is this: inflammation can turn up the 'volume' of the pain system," says Albert Rizvanov, Chief Researcher at the Laboratory of Gene and Cell Technologies.

Migraine is a multifactorial disease in which genetic predisposition plays a major role, and modeling inflammation in experiments is not simply an analog of common seasonal colds.

"In the study, we modeled an inflammatory background in an early developmental period and tested how it affects the sensitivity of pain pathways later on. In humans, many factors influence migraine—heredity, sleep, stress, hormonal changes, and lifestyle. The overall conclusion can be formulated as follows: early inflammatory exposures may potentially tune neuroimmune mechanisms so that the pain system becomes more sensitive. That's why we must speak very carefully: not that colds will cause migraine, but that inflammation may be one factor affecting symptom severity in predisposed people,'" the scientist explains.

A persistently elevated level of pro-inflammatory substances in the body can keep the trigeminal system in a state of heightened readiness.

"We showed that inflammation increases trigeminal system activity and raises reactivity to serotonin, one of the mediators involved in migraine. If a person has chronic inflammation, it may maintain an overall inflammatory background and thereby contribute to sensitization of pain pathways, that is, make it easier to trigger an attack or intensify symptoms. But this is not a universal rule. In some people the link will be noticeable, in others it won't. From a practical standpoint the conclusion is simple: controlling chronic inflammation is beneficial not only in itself, but also potentially as a way to manage migraine in patients," he adds.

The path from a fundamental discovery to a specific drug is long and complex. However, the treatment paradigm is already changing.

"To be honest, we shouldn't expect fast, revolutionary drugs. What matters is different: understanding the role of inflammation already broadens the range of approaches to migraine therapy. This is not only about classic anti-inflammatory or targeted drugs, but also about gentler, systemic ways to reduce neuroinflammation. For example, the influence of the gut microbiome on the nervous system is being actively studied today. It is known that the gut microbiota can affect the body's immune background, the level of inflammation, and even the functioning of pain and serotonergic pathways, which are directly involved in migraine. In this context, probiotics are being considered as one promising supportive tool. There are data suggesting that certain bacterial strains can reduce systemic and neuroinflammation, influence mediator production, and thereby reduce pain sensitivity and attack frequency in some patients. This is not a migraine cure in the direct sense, but potentially an element of comprehensive therapy. Future approaches to migraine treatment will likely include not only targeted drugs, but also work with the body's inflammatory background as a whole – through the immune system, metabolism, and the microbiome," believes Rizvanov.

The study does not call for creating sterile conditions for a child. On the contrary, its conclusions emphasize the importance of a responsible approach to health.

"From the standpoint of common sense and modern medicine, what matters more is not sterile protection from everything, but reasonable prevention and proper treatment. Infections in childhood are inevitable, and parents' task is to reduce the risks of severe disease and complications, follow the vaccination schedule, maintain sleep, nutrition, and recovery routines, and seek medical care in time. Our data only emphasize that pronounced inflammation can increase the sensitivity of pain pathways; therefore, 'pushing through' illness, delaying treatment, or ignoring chronic inflammatory problems is not the best strategy, especially if there is a family predisposition to migraine," he explains.

The study was supported by a grant from the Ministry of Science and Higher Education of the Russian Federation No. 075-15-2025-679. The grant's scientific supervisor is Aliya Yakubova, Senior Researcher at the Laboratory of Gene and Cell Technologies.. The work was carried out at the Department of Human and Animal Physiology of the Institute of Fundamental Medicine and Biology, headed by Guzel Sitdikova.

More information:
LPS-Induced Neuroinflammation Increases Serotonin-Evoked Activity of Trigeminal Afferents and Aggravates Mechanical Allodynia and Photophobic Behavior in Rat Migraine Model
www.mdpi.com/1422-0067/26/24/11983

Provided by Kazan Federal University