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Epigenetic regulation of chronic pain states
Epigenetic regulation of chronic pain states Chronic pain currently affects 1 in 5 European adults and is one of the most important unsolved problems in medicine today. Clinical observations have indicated that diseases or injuries of similar severity can cause different degrees of pain. Therefore, predicting whether an individual is susceptible to develop chronic pain, which would allow early and preventive treatment, is an extremely difficult challenge. This is because pain is a sensory experience not only determined by the intensity of the injury but also by a number of factors including our past experiences. Past experiences can indeed strongly influence human behaviour. For example, traumatic early life events can leave a lasting trace and influence our way of coping in stressful situations in adult life. This is due to a chemical mark, attributed to so called epigenetic mechanisms, left on the chromatin, which is the combination of DNA and proteins that make up chromosomes. In other words, epigenetic mechanisms imprint environmental experiences onto our fixed genome. These mechanisms therefore provide a bridge between the genes and the environment by refining neural networks according to experience and allow the environment to elicit long-life biological changes. Currently, my lab is exploring the hypothesis that long lasting epigenetic modifications in the dorsal horn could be responsible for the unpredictable transition from acute to chronic pain, one of the most important unsolved problems in medicine today. FKBP51, a stress regulator that modulates chronic pain. My research into the regulation of pain states by epigenetic mechanisms has led to the identification of a potential new target for the management of pain. My team has indeed elucidated the role of the protein FKBP51 in the maintenance of chronic pain states. The mechanisms that connect mood disorders and chronic pain states have remained poorly understood but a regulator common to both conditions now appears to be the FKBP51 protein. FKBP51 modulates the glucocorticoid receptor (GR) sensitivity and is therefore important for the regulation of the stress response. Single nucleotide polymorphisms of the FKBP5 gene have been repeatedly associated with anxiety related disorders, including major depression and post-traumatic stress disorder (PTSD). Moreover, inhibition or deletion of the protein in mice reduced anxiety-related behaviour. Our recent study published in Science Translational Medicine (MaiarĂ¹ et al. 2016; link below) has shown that mice that lack the protein FKBP51 have reduced chronic pain after joint inflammation and nerve damage. Moreover, deletion of FKBP51 specifically at the level of the spinal cord using silencing RNA (siRNA) could interrupt a pre-existing chronic pain states. This suggested that FKBP51 could regulate pain independently from its effect on mood, which presumably happens at brain level. Crucially, it was recently reported that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced after motor vehicle collision and sexual assault, suggesting that targeting FKBP51 would be beneficial for the treatment of chronic pain in humans. The first specific inhibitors of FKBP51 have been recently developed by our collaborator, Professor Felix Hausch, at the Max Planck Institute of Psychiatry, Munich (Gaali et al. 2015, Nat. Chem. Biol.). These inhibitors were able to reduce anxiety related behaviour in mice in vivo. We have tested one of these compounds in our traditional rodent paradigms and found that FKBP51 antagonism was as effective as local or global deletion in relieving inflammatory and neuropathic pain. We are currently testing these inhibitors in clinically relevant models and we are also looking into the relationship between chronic pain and mood disorders.
2 Researchers
3 External Collaborators
  • Dr Felix Hausch
    Max Planck Institute - United Kingdom
  • Dr Mathias Schmidt
    Max Planck Institute - United Kingdom
  • Prof Gerhard Winter
    Ludwig Maximilian University of Munich - Germany
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