<p>Altered BDNF Methylation in Patients with Chronic Musculoskeletal Pain and High Biopsychosocial Complexity</p>

Abstract

The INTERMED instrument, which was developed to measure patient's biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status. Patients and Methods: Fifty-eight chronic musculoskeletal pain patients (CMSP) were enrolled in the study. DNA was extracted from blood samples, the methylation levels of 13 CpG sites in the BDNF promoter were measured by pyrosequencing, and association studies with various patient parameters and the INTERMED scores were performed. Results: Interestingly, a negative correlation (−0.40) was found between the total INTERMED scores and the average CpG methylation values of the BDNF gene, but no correlation was observed with the severity of pain, degree of anxiety, depression, or kinesiophobia and catastrophism. Moreover, the association was independent of age, sex and level of comorbidities. Conclusion: This result shows that CMSP, in association with its biopsychosocial context, epigenetically decreases the degree of methylation of the BDNF promoter and should therefore increase the level of BDNF transcription. It also suggests a role of the INTERMED tool to detect a relationship between the BPS complexity and the epigenetic control of a target gene. The possible upregulation of BDNF expression might be, at least in part, the signal for chronic pain-induced central sensitization (CS). This could partly explain why patients with a higher level of complexity feel more pain than those with lower complexity.

The influence of cultural and religious factors on cross-national variations in the prevalence of chronic back and neck pain: an analysis of data from the global burden of disease 2019 study

“…Uncertainty avoidance measures the extent to which a society is able to tolerate ambiguous or uncertain situations; high scores on this dimension imply that a country's culture would have rigid codes of conduct and be intolerant of unconventional ideas or behaviour ( 88 ). In a study of patients with chronic musculoskeletal pain, a measure of the complexity of each patient's psychosocial situation was found to be associated with altered methylation of the brain-derived neurotrophic factor (BDNF) gene ( 89 ). BDNF is an important regulator of neural plasticity, and plays a central role in several psychological processes related to chronic pain, including stress response, learning and memory.…”

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation

“…While genetic alterations offer a partial explanation for chronic pain, the emerging field of epigenetics provides a more nuanced and dynamic perspective by unraveling the gene expression patterns associated with chronic pain [154,155]. Recent studies revealed that epigenetic mechanisms, including histone acetylation [156], non-coding RNAs [156,157], and DNA methylation [127,158,159], can influence the expression of BDNF (Figure 2, Table 3). These epigenetic modifications may contribute to the pathogenesis and symptomatology of chronic pain.…”

Pathophysiology of musculoskeletal pain: a narrative review

“…Psychosocial factors also influence gene expression in chronic musculoskeletal pain: for example, higher levels of BDNF expression are related to higher biopsychosocial complexity and can be linked to an increased risk of central plasticity. 62 Other research suggests that different micro-ribonucleic acid (micro-RNA) fragments have higher expression in neuropathic versus nociceptive musculoskeletal pain. 63 …”

“…61 Psychosocial factors also influence gene expression in chronic musculoskeletal pain: for example, higher levels of BDNF expression are related to higher biopsychosocial complexity and can be linked to an increased risk of central plasticity. 62 Other research suggests that different micro-ribonucleic acid (micro-RNA) fragments have higher expression in neuropathic versus nociceptive musculoskeletal pain. 63 In summary, the assessment of and therapeutic development for chronic musculoskeletal pain must be global, focusing not only on molecular targets but also on demographic, psychological, and contributing social factors.…”