Many millions of people suffer with debilitating headache and facial pain disorders. A common feature of these disorders is that they substantially worsen at certain times of day.
Professor Cader has shown that proteins known as cryptochromes that are involved in the regulation of the body's 24-hour circadian rhythm are also involved in the regulation of pain severity. In this project he sets out to advance understanding of how this regulation works, and how it could be targeted in order to reduce pain.
Based on strong preliminary data, and following rigorous assessment as part of our competitive grant round, this project was recommended for its potential impact in an area of high unmet need.
An estimated 20 million people in the UK are affected by 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 group of patients there are no meaningful treatments at all. This leads to a considerable burden of pain, suffering and disability for the individual and very often this will continue over many years.
A feature of these headache and facial pain conditions is that they substantially worsen at certain times of day; this can interfere with daily activities, work and sleep.
Work by Professor Cader and colleagues has identified powerful time-keeping mechanisms present in pain nerves that could be harnessed to help reduce headache and pain. This approach is different to any current treatments and, because it uses the body’s own mechanism, could have the potential to be both safe and more effective than other approaches at reducing headache/pain severity and associated disability.
Cells have a time-keeping mechanism that ensures that they are functioning in the right way at different times over the day and night. This mechanism is a molecular clock that has 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 particular time of day.
Professor Cader and colleagues have shown that the cryptochromes play a key role in pain responsiveness. They have also demonstrated that a chemical that acts on the cryptochromes to make them more stable can reduce pain responses.
From this starting point, they would like to find chemicals that can achieve the same effect on pain but without interfering with the clock. These chemicals could then lead to the development of new drugs, translating to a safe pain treatment. To get here, we need a better understanding of the clock mechanism.
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 activity of the cells' pain response mechanisms, how this activity changes between different timepoints, 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 made considerable progress in unravelling these mechanisms.
This project will add significant new knowledge on the detailed mechanism by which this variation is regulated. This will enable the development of drugs that can target this mechanism as a pain and headache treatment.
Professor Zameel Cader is a Professor of Neuroscience and Neurology at the University of Oxford, and a Consultant Neurologist with a special interest in headache disorders. He has been working 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, and have demonstrated that the project described 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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