Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics

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.

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“…With the rapid development of treatments, acting through modulation of epigenetic modifications, our approach may turn out to be promising. 44…”

Section: Discussionmentioning

confidence: 99%

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

Paoloni-Giacobino¹,

Lüthi²,

Stenz³

et al. 2020

JPR

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“…The anti-inflammatory and anti-fibrogenesis role of givinostat has been revealed in several acute liver disease models, yet whether HDAC inhibitors could alleviated inflammation and fibrosis in chronic disease requires further study. Recent studies have demonstrated that givinostat could interfere inflammation and fibrosis progression in different diseases like intestinal epithelial inflammation or osteoarthritis (39,40). This prompted us to examine whether givinostat could serve as a potential candidate for treatment of NASH, which remains undetermined up to now.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

Huang

Fan

et al. 2020

Preprint

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Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that causes worldwide morbidity and mortality, yet there is still a lack of pharmacological therapies. Liver inflammation is an important contributor for disease progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH).We identified HDAC inhibitor givinostat as a potent inhibitor of macrophages inflammatory activation, and aimed to evaluate the therapeutic potential of givinostat for treatment of NASH. Daily administration of givoinostat (10mg/kg) alleviated inflammation and attenuated hepatic fibrosis in methionine-and choline-deficient diet (MCD)-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In hepatocyte givinostat reduced palmitic acid induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in fructose, palmitate, cholesterol diet (FPC) induced NASH mice. Givinostat attenuated hepatic steatosis, inflammation as well as liver injury in FPC-induced NASH. In conclusion, givinostat appears to be efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for treatment of human NASH.

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“…Prescribing strong opioids in patients with chronic pain requires precision in management. Both genetic and epigenetic factors contribute to the development of drug resistance in patients with chronic pain (6,7). Genetic variation in receptors contributes to the various responses to opioids within or between individuals (8).…”

Section: Wwwpainphysicianjournalcommentioning

confidence: 99%

Establishment of an Individualized Chronotherapy, Autonomic Nervous System, and Variability-Based Dynamic Platform for Overcoming the Loss of Response to Analgesics

2021

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Background: Control of chronic pain and mainly the partial or complete loss of response to analgesics is a major unmet need. Multiple mechanisms underline the development of tolerance to analgesics in general and specifically to opioids. The autonomic nervous system (ANS) plays a role in the development of analgesic tolerance and chronobiology. Objectives: To review the mechanisms associated with the development of nonresponsiveness to analgesics. Study Design: Literature review. Setting: The review is followed by a description of a new method for overcoming resistance and improving the response to analgesics. Methods: Conducted a detailed review of the relevant studies describing the mechanisms that underlie tolerance to pain medications, and the potential roles of the ANS and chronobiology in the development of drug resistance. Results: The autonomic balance is reflected by heart rate variability, an example of a fundamental variability that characterizes biological systems. Chronotherapy, which is based on the circadian rhythm, can improve the efficacy and reduce the toxicity of chronic medications. In this article, we present the establishment of an individualized variability- and chronobiology-based therapy for overcoming the compensatory mechanisms associated with a loss of response to analgesics. We describe the premise of implementing personalized signatures associated with the ANS, and chronobiology, as well as with the pathophysiology of pain for establishing an adaptive model that could improve the efficacy of opioids, in a highly dynamic system. Limitations: The studies presented were selected based on their relevance to the subject. Conclusions: The described variability-based system may ensure prolonged effects of analgesics while reducing the toxicity associated with increasing dosages. Key words: Painkillers, opioids, drug resistance, compensatory mechanisms

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Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics

Cited by 22 publications

References 160 publications

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

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

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

Establishment of an Individualized Chronotherapy, Autonomic Nervous System, and Variability-Based Dynamic Platform for Overcoming the Loss of Response to Analgesics

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