Research title: STRESS INTOLERANCE IN PATIENTS WITH CHRONIC WIDESPREAD PAIN: ARE EPIGENETIC MECHANISMS THE ANSWER TO THE MYSTERY?
Stress can be defined as the physiological and biological response of the body to any situation that is perceived as threatening or exceeding one’s ability to cope with it. The bi-directional link between stress and chronic pain has been extensively studied (1). Stress and pain are highly comorbid, and show significant overlap in both conceptual and biological processes (2). Patients with CWP experience stress intolerance – that is, an exacerbation of symptoms in response to stress (3).
A recent review showed that an altered stress response predicted chronic pain and poor health at a long-term follow-up (1 year)(4). Interestingly, the autonomic nervous system (ANS) is also dysregulated in patients with CWP at baseline and in response to stress (5, 6). The ANS regulates several crucial physiological functions such as blood vessel activity, blood pressure, and heart rate via the release of catecholamines such as adrenaline, noradrenaline, and dopamine. Blood pressure appeared to be associated with pain intensity (7) and heart rate variability is consistently decreased in patients with CWP (8, 9). Finally, preclinical studies showed that elevated levels of catecholamines are required for the induction and maintenance of stress-induced hyperalgesia – a core component of stress intolerance in patients with CWP (10).
Catecholamine levels are regulated by the activity of enzymes that synthesise and degrade them. Interestingly, catecholamine-degrading enzymes have been linked to both stress and pain, and are thus strong candidates to be involved in stress intolerance in patients with CWP. For instance, genetic polymorphisms affecting catechol-O-methyltransferase (COMT) activity have been associated with increased stress responsiveness and pain sensitivity in both animals and humans (11-14). Similarly, other catecholamine-degrading enzymes, monoamine oxidase A and B (MAO-A/B), have also been implicated in stress responses (particularly after mental stress)(15, 16) and pain (17-19).
Given the many associations between catecholamine-degrading enzymes, stress, and pain, mechanisms affecting the activity of these enzymes seems to be crucial in stress intolerance in patients with CWP.
A KEY REGULATORY ROLE FOR EPIGENETICS IN STRESS INTOLERANCE
The effect of stress on pain (i.e. hypo- or hyperalgesia in response to stress) depends on the magnitude of the individual stress response (20). Genetic polymorphisms can explain at least part of between-subject variability in stress responses and pain, but they cannot explain within-subject variability (21, 22). Epigenetic changes strong candidates to explain intra-subject variability, as they are dynamic mechanisms, responsive to environmental changes and the context (23). The field of epigenetics is rapidly growing as it represents a new set of dynamic biological mechanisms able to change gene expression without interfering with the DNA sequence itself (24). Epigenetic modifications contribute to the pathogenesis of neurological disorders, psychiatric illnesses and cancer (25), and already led to breakthrough research findings and innovative treatments in other fields (26). However, only few studies investigated epigenetic mechanisms in relation to CWP (27), and no study assessed this in the context of stress intolerance, even though epigenetic mechanisms are influenced by stressful exposures (28). DNA methylation – the bestknown epigenetic mechanism – of COMT, MAO-A and MAO-B genes is in fact influenced by early-life stress and is altered in patients with stress-related conditions (29-31). However, such stress-related DNA methylation patterns have not been investigated in patients with CWP. Hence, our project aims to unravel stress intolerance in patients with CWP by investigating COMT, MAO-A and MAO-B methylation, the activity of catecholamine-degrading enzymes, and ANS activity at baseline and in response to mental stress. Our findings will provide targetable mechanisms and enable the development of innovative treatments for stress intolerance and CWP in general.
OUR RESEARCH PROPOSAL
DNA methylation will be assessed at baseline and in response to stress on three target genes encoding for the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase A and B (MAO-A/B) via a randomised cross-over study. The regulatory role of DNA methylation will be researched in relation to COMT, MAO-A and MAO-B activity, neurophysiological measures, and stress-induced symptom changes in patients with CWP. Epigenetic mechanisms not only improve our understanding of stress and pain pathophysiology, but are also targetable processes and thus provide the substrate to develop innovative treatments. Our project will be the largest study emplying a comprehensive (clinical, neurophysiological, and biological) assessment, and targeting DNA methylation in patients with CWP. It will also be the first study linking DNA methylation to stress intolerance and neurophysiological outcomes in people with CWP.