Altered Brain Expression of DNA Methylation and Hydroxymethylation Epigenetic Enzymes in a Rat Model of Neuropathic Pain

Abstract

The role of epigenetics in chronic pain at the supraspinal level is yet to be fully characterized. DNA histone methylation is crucially regulated by de novo methyltransferases (DNMT1-3) and ten-eleven translocation dioxygenases (TET1-3). Evidence has shown that methylation markers are altered in different CNS regions related to nociception, namely the dorsal root ganglia, the spinal cord, and different brain areas. Decreased global methylation was found in the DRG, the prefrontal cortex, and the amygdala, which was associated with decreased DNMT1/3a expression. In contrast, increased methylation levels and mRNA levels of TET1 and TET3 were linked to augmented pain hypersensitivity and allodynia in inflammatory and neuropathic pain models. Since epigenetic mechanisms may be responsible for the regulation and coordination of various transcriptional modifications described in chronic pain states, with this study, we aimed to evaluate the functional role of TET1-3 and DNMT1/3a genes in neuropathic pain in several brain areas. In a spared nerve injury rat model of neuropathic pain, 21 days after surgery, we found increased TET1 expression in the medial prefrontal cortex and decreased expression in the caudate-putamen and the amygdala; TET2 was upregulated in the medial thalamus; TET3 mRNA levels were reduced in the medial prefrontal cortex and the caudate-putamen; and DNMT1 was downregulated in the caudate-putamen and the medial thalamus. No statistically significant changes in expression were observed with DNMT3a. Our results suggest a complex functional role for these genes in different brain areas in the context of neuropathic pain. The notion of DNA methylation and hydroxymethylation being cell-type specific and not tissue specific, as well as the possibility of chronologically differential gene expression after the establishment of neuropathic or inflammatory pain models, ought to be addressed in future studies.

The Epigenetics of Neuropathic Pain: A Systematic Update

“…Over this long period, time point-specific differential methylation of individual genes at the promoter regions was revealed, affecting numerous pain-related genes. In rats with SNI, TET1 expression was increased in the prefrontal cortex, and DNMT1 expression was increased in the hippocampus [21,22]. In the partial sciatic nerve ligation (PSNL) model of mice, the reduced global DNA methylation in the prefrontal cortex and in the periaqueductal grey matter, which has been confirmed and correlated with mechanical allodynia and cold allodynia [23].…”

A Step Forward: About the Progresses Made in the Second Edition of the Special Issue “The Multiple Mechanisms Underlying Neuropathic Pain”

“…Thus, the persistence of pain memory is a factor responsible for the transition to chronic pain and the epigenetic changes that occur in different brain areas, a poorly investigated but substantial mechanism. These authors [2] investigated the mRNA expression of some key genes in different brain areas (e.g., hippocampus, medial prefrontal cortex, caudate-putamen and amygdala) and their association with the consolidation of NeuP. The key point concerns the epigenetic modifications, particularly DNA histone methylation, under the control of DNA methyltransferase (DNMTs) 1-3, so-called de novo DNMTs, and ten-eleven translocation dioxygenases (TET1-3) that have a role in passive and active demethylation [5].…”

“…Compared to the first edition, some themes, such as the discussion of the role of the Insular cortex (ICx) in pain processing, have been reintroduced, but interestingly, the Special Issue was authored by another expert in the field [1] who utilized a different perspective to explore this issue. However, before turning our gaze to the insular function and its involvement in chronic pain, we annotated that this second edition can improve our information concerning neuropathic pain (NeuP) by dealing with the epigenetic changes occurring at the supraspinal level in different brain areas [2] and the maladaptive neuroplasticity and central mechanisms that underlie a neglected form of chronic pain that is identified as complex regional pain syndrome (CRPS) [3]. On the other hand, these heterogeneous contributions well reflect the "elusive" nature of pain and, in particular, NeP, which is characterized by multiple etiologies (e.g., traumatic, drug-therapy-associated, viral and endocrine causes), sensory alterations (e.g., paresthesia and numbness), the loss of function (e.g., motor function) and, above all, the partial efficacy or total inadequacy of the drugs used to treat this chronic condition [4].…”

“…The discussion of the "origin" of NeP often neglects the fact that Nep may have either central nervous system or peripheral causes. Likewise, the cognitive and affective aspects in terms of NeP should not be undervalued in explaining the progression from acute to chronic pain, and the paper by Rodrigues and colleagues [2] appropriately reminds us of the fact that specific brain areas are involved in both memory processing and affective features of pain, such as the hippocampus, prefrontal cortex, anterior cingulate cortex, ventral tegmental area and the nucleus accumbens. Thus, the persistence of pain memory is a factor responsible for the transition to chronic pain and the epigenetic changes that occur in different brain areas, a poorly investigated but substantial mechanism.…”

“…By collecting demonstrations that, depending on brain areas, DNA methylation is critical for the establishment of chronic pain [2], and that the brainstem is involved in pain processing (via the study of habituation to nBR) [3], that MOR-DOR multitargeting drugs can produce anti-inflammatory effects through astrocyte/microglia functional uncoupling [8], that the study of ICx can improve our knowledge not only of the different components of pain processing and experience [1] but also about the gender gap in pain susceptibility and response to therapy [13], we believe that this second volume of the SI "The Multiple Mechanisms Underlying Neuropathic Pain" has addressed many of the planned objectives.…”