Many millions of people suffer from debilitating headache and facial pain disorders. A common feature of these disorders is that they worsen at certain times of day.
Professor Cader has shown that proteins called cryptochromes, which help regulate the body's 24-hour circadian rhythm, are also involved in the regulation of pain severity. In this project he aims to advance understanding of how this regulation works, and how it could be targeted to reduce pain.
An estimated 20 million people in the UK have a headache or facial pain disorder, two in five adults.
Many patients with these disorders remain insufficiently treated, despite currently available treatments. For a substantial number of patients, no effective treatments exist. This leads to a considerable burden of pain, suffering and disability for the individual.
A feature of these headache and facial pain conditions is that they worsen at certain times of day; this can interfere with daily activities, work and sleep.
Professor Cader and colleagues have identified powerful time-keeping mechanisms present in pain nerves that could be harnessed to help reduce headache and pain. This approach differs from any current treatments and, because it uses the body’s own natural mechanisms, could be both safer and more effective than other approaches at reducing headache/pain severity and associated disability.
Cells have a time-keeping mechanism that ensures that they function in the right way at different times of day and night. This mechanism is a molecular clock with a 24-hour rhythm. A group of proteins called the cryptochromes play a key role in the maintenance of this rhythm.
Our sensitivity to pain is also governed by these daily rhythms so that pain conditions often worsen at a certain time of day.
Professor Cader and colleagues have shown that the cryptochromes play a key role in pain responsiveness. They have also found that a chemical that acts on the cryptochromes to make them more stable can reduce pain responses.
From this starting point, they want to find chemicals that can achieve the same effect on pain but without disrupting the clock. Such chemicals could lead to the development of new drugs, translating to a safe pain treatment. To get here, we need to understand the clock mechanism better.
The team will use a technology called induced pluripotent stem cells (iPSC). These cells can be turned into any cell type in the human body, and in this project will be used to produce human pain nerve cells. This will enable them to study the cells' pain response mechanisms, how this activity changes over time, and which other proteins are involved.
This will give new insight into the mechanisms underlying the circadian rhythm of pain, and a possible new approach to treatment.
Whilst the 24-hour variation in pain severity for headache and facial pain disorders is well-established, the underlying mechanisms have been unknown. Professor Cader and colleagues have already made considerable progress in unravelling these mechanisms.
This project will add valuable new knowledge about how this variation is regulated. This will enable the development of drugs that can target this mechanism as a pain and headache treatment, offering hope to people like Marleen, who suffers from chronic migraine.
"I have chronic migraine, so have a headache most days. I get an intense pain on one side of my head, this can be throbbing or very diffuse but intense pain, or the feeling that knives are being wedged into my brain. I am often nauseous but rarely vomit. I feel utterly exhausted when I am going to get a migraine, or for days after I've had one."
Professor Zameel Cader is a Professor of Neuroscience and Neurology at the University of Oxford, and a Consultant Neurologist specialising in headache disorders. He worked for many years on the causes of migraine and new treatment approaches. His research group has specific expertise in human induced pluripotent stem cells, which will be used extensively in this project. He is also a principal investigator for the Sleep and Circadian Neuroscience Institute at Oxford, which provides access to a wealth of relevant expertise.
He is collaborating on this project with Professor Martin Larsen of the University of Southern Denmark, a world-leader in protein studies who has established widely used methods in the field.
The pair have already been working together to undertake some initial protein studies, demonstrating that their project is feasible. They have the expertise, lab resources, new techniques and data analysis skills to complete the project successfully and answer the research questions.
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