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Pethő, G.; Kántás, B.; Horváth, �.; Pintér, E. The Epigenetics of Neuropathic Pain. Encyclopedia. Available online: (accessed on 18 June 2024).
Pethő G, Kántás B, Horváth �, Pintér E. The Epigenetics of Neuropathic Pain. Encyclopedia. Available at: Accessed June 18, 2024.
Pethő, Gábor, Boglárka Kántás, Ádám Horváth, Erika Pintér. "The Epigenetics of Neuropathic Pain" Encyclopedia, (accessed June 18, 2024).
Pethő, G., Kántás, B., Horváth, �., & Pintér, E. (2023, December 20). The Epigenetics of Neuropathic Pain. In Encyclopedia.
Pethő, Gábor, et al. "The Epigenetics of Neuropathic Pain." Encyclopedia. Web. 20 December, 2023.
The Epigenetics of Neuropathic Pain

Epigenetics deals with alterations to the gene expression that occur without change in the nucleotide sequence in the DNA. Various covalent modifications of the DNA and/or the surrounding histone proteins have been revealed, including DNA methylation, histone acetylation, and methylation, which can either stimulate or inhibit protein expression at the transcriptional level.

animal models DNA methylation epigenetics histone acetylation

1. Basic Concepts of Epigenetics

It is an old recognition that different cell types of the body that possess the same nucleotide sequence in the deoxyribonucleic acid (DNA) have distinct structures and functions, and these features are primarily determined by differences in the expression profile of the genes, leading to changes in the cellular amount and function of proteins. Epigenetics deals with modifications to the gene expression that occur without alteration of the nucleotide sequence in response to external (diet, lifestyle, eventual drug exposure, etc.) or internal factors (e.g., sex, race, development, aging, pathological states). Epigenetic processes can be initiated by altering the chromatin substance composed of DNA and histone proteins. Chromatin is built up from repeating structural units called nucleosomes. In each nucleosome, about 140 nucleotide-pair-long DNA is wrapped around an octamer complex of histone proteins, including 2–2 copies of H2A, H2B, H3, and H4. The H1 and H2 proteins are bound to the DNA as it enters the nucleosomes and keep in place the DNA that has wrapped around the nucleosome core, and they also bind to the linker DNA connecting the adjacent nucleosomes. Chromatin can exist in two forms. Heterochromatin is a condensed configuration with short free segments of DNA (forming a beads-on-a-string structure) repressing transcription. Euchromatin is a more relaxed configuration in which longer free DNA segments allow for the binding of transcription factors, thus promoting transcription.
Epigenetic processes lead to covalent modifications of the DNA in the form of methylation or alteration of the histone proteins by methylation, acetylation, phosphorylation, etc., which result in an increase or decrease in gene expression, typically at the transcriptional level [1]. Several enzymes responsible for attaching and removing these epigenetic molecular marks (so-called writers and erasers, respectively) and protein factors recognizing them (so-called readers) have been identified and characterized.

2. The Role of DNA Methylation/Demethylation in Neuropathic Pain

2.1. General Principles

DNA methyltransferase (DNMT) enzymes attach a methyl group to carbon 5 of a cytosine base adjacent to a guanine residue, a so-called CpG site, which is typically concentrated at the promoter region of genes that form CpG islands [2]. There are several forms of DNMTs; DNMT1, as a maintenance enzyme, functions during cell division to copy the methylation pattern of the old DNA strand onto the complementary new one, whereas DNMT3a and DNMT3b mediate de novo methylation in response to the above-mentioned external and internal factors. Methylation of CpG islands typically causes gene repression, partly by preventing the binding of transcription factors and partly by functioning as docking sites for 70 amino acid-long methyl-CpG-binding domain (MBD) proteins, inhibiting transcription. These epigenetic readers include methyl-CpG-binding protein 2 (MeCP2) and a series of MBD 1–6 proteins, and they work by recruiting other transcriptional repressors such as histone deacetylase or histone methyltransferase enzymes (see later). DNMT2 is a homolog that methylates cytosine bases in the transfer RNA.
DNA demethylation can be passive or active. The passive way refers to the absence of methylation of newly synthesized DNA strands by DNMT1 during repeated DNA replication cycles. Active demethylation occurs without DNA replication by 10 to 11 translocation (TET) methylcytosine dioxygenase enzymes, which are so-called editors that are able to modify epigenetic marks. TET enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the CpG dinucleotide. Furthermore, TET1 itself, as well as the formed 5-hydroxymethylcytosine, both prevent the binding of DNMT to CpG sites. As these activities contribute to DNA demethylation, TET enzymes can also be regarded as epigenetic erasers [3].

2.2. Expression of Elements of the DNA Methylation Machinery in Primary Sensory Neurons

Proteins involved in DNA methylation/demethylation have been localized to the dorsal root ganglia (DRG) that contains the cell body of primary sensory neurons, including nociceptive ones, and in the spinal dorsal horn, comprising the central terminals of (nociceptive) primary afferent neurons and the bodies of other cell types. Concerning the writer proteins, all three forms of DNMTs (DNMT1, DNMT3a, and DNMT3b) are expressed in the DRGs under normal conditions [4][5][6][7]. A predominantly neuronal expression in both peptidergic and non-peptidergic primary sensory neurons was detected. DNMT3a and DNMT3b were also revealed in the dorsal horn [8]. Considering the reader proteins, MeCP2 expression in the lumbar spinal cord of rats was revealed—mainly in neurons, much less in glial cells [4][9]. Similarly, MBD1 expression was detected in both peptidergic and non-peptidergic sensory neurons, but not in glial cells of the mouse DRG [10]. Regarding the eraser proteins, TET proteins were also detected in the DRG of mice: TET1 and TET3 only in neurons, whereas TET2 was also in non-neuronal cells; TET3 was predominantly located in presumably nociceptive small- and medium-sized neurons [11]. Accordingly, a 5hmC signal was detected in nearly all DRG neurons of mice. TET1 expression was also observed in the dorsal horn neurons of rats [12].

2.3. Global Changes in DNA Methylation under Neuropathic Conditions

An early study on rats with chronic constriction injury (CCI) of the sciatic nerve revealed an increased global DNA methylation and upregulation of MeCP2 in the lumbar spinal cord on day 14 after nerve injury [9]. These changes were inhibited by intrathecally applied 5-azacytidine, a nonselective inhibitor of DNMT enzymes. The latter agent also reduced CCI-evoked mechanical allodynia and heat hyperalgesia, suggesting that CCI may lead to epigenetic silencing of some putative antinociceptive genes via DNA methylation. In a genome-wide analysis of the spinal cords of rats with CCI, 638 hypermethylated and 567 hypomethylated sites within promoter regions were revealed [13].
One day after spinal nerve ligation (SNL), in DRGs of rats, plastic changes of the DNA methylation pattern were revealed with predominant (80%) hypermethylation of CpG sites observed, not only at the promoter regions of genes, but also in exons and introns as well as outside of genes [14]. There was no clear correlation between the direction of change of the methylation status and the level of gene expression. In the same model, the genome-wide analysis revealed both DNA hypermethylation and hypomethylation in the affected DRGs 3 days after injury [15]. In contrast, three weeks after injury, DNA hypomethylation prevailed predominantly outside CpG islands and in introns, intergenic regions, and repeats. Interestingly, DNA hypermethylation was more typical in the spinal cord and prefrontal cortex. The nerve injury-induced methylation reprogramming correlated with increased gene expression in the DRGs. These data suggest that DNA hypomethylation in the DRG prevails in this model of neuropathic pain.
In the spared nerve injury (SNI) model of rats, involving ligation of the tibial and peroneal nerves but sparing the sural nerve, messenger ribonucleic acid (mRNA) expressions of DNMTs and MeCP2 were downregulated in the dorsal horn, the latter also in the ipsilateral, injured DRG [4]. In accordance, the 5hmC signal, indicating DNA demethylation, was increased at the ipsilateral DRGs of mice with SNI, and TET3 expression was increased, as opposed to TET1 or TET2 expression [11]. All these alterations point to nerve injury-evoked DNA hypomethylation in this model. The genome-wide analysis in mice with SNI revealed in the DRG a redistribution of MeCP2 binding to transcriptionally relevant regions [16].
The prefrontal cortex is of crucial importance for chronic pain states as an integrator area. In early studies in this field employing the SNI model in mice or rats six or nine months after nerve injury, a decreased global DNA methylation level was detected in the prefrontal cortex and amygdala, but not in other brain areas [17][18]. Accordingly, DNA hypomethylation in this structure correlated with mechanical allodynia and cold hyperalgesia. Chronic post-treatment of SNI mice with the methyl donor S-adenosylmethionine diminished nerve injury-induced mechanical hypersensitivity, indirectly supporting the role of DNA methylation [19]. In a long-term follow-up study on SNI mice, the global DNA methylation pattern in the prefrontal cortex was assessed 1 day, 2 weeks, 6 months, and 1 year after nerve injury [20]. 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]. Using differentially methylated regions analysis, 2451 hypermethylated and 1991 hypomethylated gene promoters were identified. In addition, expressions of DNMT1, DNMT3a, and DNMT3b were decreased as well. Acupuncture could restore both the DNA hypomethylation in the prefrontal cortex and the nociceptive hyperresponsiveness. In a mouse model of neuropathic pain based on unilateral transection of the tibial nerve, global DNA methylation was increased bilaterally in the primary somatosensory cortex [24].
Paclitaxel-induced neuropathy caused no significant alterations in DNA methylation levels in the DRG, but, in mice with streptozotocin-induced diabetes, 376 genes were hypermethylated and 336 were hypomethylated at CpG sites of promoter regions in the DRGs [15][25]. In a recent human study, the genome-wide analysis revealed differentially methylated regions in the DNA obtained from blood cells [26]. The methylation pattern of patients with neuropathic pain was different, not only compared to healthy controls, but also to patients suffering from nociceptive pain.

2.4. Proteins Regulated by DNA Methylation in Neuropathic Conditions

2.4.1. Opioid Receptors

Gi protein-coupled mu, delta, and kappa opioid (MOP, DOP, and KOP, respectively) receptors mediate the analgesic effects of both therapeutically applied opioids and endogenous opioid peptides. In particular, the MOP receptor is subject to epigenetic regulation by DNA methylation. As shown in mice with CCI, morphine’s peripheral and spinal antinociceptive effects were decreased due to the downregulation of the MOP receptor in the DRG and the spinal cord [27][28]. Increased methylation at the proximal promoter of the MOP receptor gene was revealed in DRG neurons, along with MeCP2 upregulation. DNMT inhibition by 5-aza-deoxycytidine or knockdown of MeCP2 prevented MOP receptor downregulation in DRG and the spinal cord and restored the antinociceptive potency of morphine reduced by nerve injury. Furthermore, the octamer transcription factor 1 (OCT1) overexpression in DRG neurons was also involved in the CCI-evoked upregulation of DNMT3a and downregulation of MOP receptors [29]. Similar results were obtained regarding the spinal cord: CCI-induced heat hyperalgesia was associated with increased DNMT3a expression, the enhanced methylation level of the proximal promoter of the MOP receptor gene, and decreased MOP receptor expression [30]. All these alterations were reduced by intrathecally applied RG 108, a nonselective and irreversible DNMT inhibitor.
Consonant results were obtained in the SNL model of rats and mice. DNMT3a upregulation led to increased DNA methylation at the promoter region of the MOP receptor gene and downregulation of MOP (and KOP) receptors in the injured DRG, along with the development of tolerance to the antinociceptive effect of morphine [5][10]. In addition, a role for the reader protein MBD1 was also established, as it was upregulated in the injured DRG. DNMT3a was recruited by MBD1 to the promoter of the respective genes and involved in the transcriptional repression of the MOP receptor. In either MBD1 knockout or MBD1 knockdown (by short hairpin RNA (shRNA)) mice, the SNL-evoked mechanical allodynia, heat hyperalgesia, and cold allodynia were diminished. The SNL-induced promoter hypermethylation and downregulation of the MOP receptor gene were counteracted by microinjection of herpes simplex virus, expressing TET1 mRNA into the injured DRG [31]. This overexpression of TET1 restored the diminished analgesic efficacy of morphine and counteracted morphine tolerance induced by nerve injury.
All the above data provide evidence that hypermethylation of the MOP receptor gene promoter leads to transcriptional repression of MOP receptors with two consequences: induction of hyperalgesia, likely by reducing the antinociceptive effects of endogenous opioids, along with a diminishment of the antinociceptive effect of the applied opioid.

2.4.2. K+ Channels (Kv1.2, K2p1.1)

K+ channel opening typically causes an outward current, leading to membrane hyperpolarization and consequent neuronal inhibition. Conversely, inhibition or downregulation of K+ channels induces neuronal hyperexcitability via different mechanisms, including reduction of the total K+ current, increasing the resting membrane potential, reducing the current threshold for action potential, and increasing the number of evoked action potentials. Extensive evidence exists that decreased expression of various K+ channels contributes to neuropathic pain. For two types of them, the voltage-gated Kv1.2 channels and the two-pore-domain K+ channels (K2P), epigenetic regulation by DNA methylation in neuropathy has been revealed. In rats with SNL and/or CCI, an increased expression of DNMT3a but not DNMT3b in the injured DRG was observed [6][29]. Evidence has been provided that upregulation of OCT1 in the corresponding ipsilateral DRG but not in the spinal cord was involved in this response. OCT1 was predominantly localized in both large and small DRG neurons, including peptidergic and non-peptidergic small ones. In the DRG, DNMT3a directly inhibits the expression of the Kv1.2 channels by methylation at the promoter region of the Kv1.2 gene. These data suggest that nerve injury upregulates DNMT3a in DRG neurons involving OCT1 action, which leads to enhanced methylation of the promoter of the Kv1.2 gene, resulting in Kv1.2 downregulation. A role for the reader protein MBD1 was also revealed in mice with SNL [10]. It was shown that DNMT3a was recruited by the upregulated MBD1 to the promoter of the Kv1.2 channel gene and was involved in the transcriptional repression of this channel. The SNL-induced promoter hypermethylation and downregulation of the Kv1.2 gene were rescued by artificial TET1 overexpression in the injured DRG [31].
Similar results were obtained upon implantation of prostate cancer cells into the rat tibia, which led to mechanical allodynia, heat hyperalgesia, and cold allodynia, along with increased DNMT3a (but not DNMT3b) expression and a decreased Kv1.2 channel expression in the ipsilateral dorsal horn (but not DRG) [8]. Pharmacological inhibition (by decitabine, a nonselective DNMT inhibitor) or genetic knockdown (by shRNA) of DNMT3a prevented tumor cell-induced Kv1.2 channel downregulation and reversed the behavioral responses.
In a complex study employing SNL, CCI, and axotomy models, evidence for involvement of DNMT1, the primary maintenance DNMT, in neuropathic pain has been provided [7]. DNMT1 was upregulated in the DRG in response to nerve injury through the transcription factor cyclic adenosine monophosphate (AMP) response element-binding (CREB) protein, which was shown to directly bind to the promoter of the DNMT1 gene, leading to transcriptional activation. DNMT1 was shown to reduce Kv1.2 channel expression (but not MOP or KOP receptor levels) in the injured DRG by methylating three sites of the Kv1.2 gene. These data suggest that DNMT1 may be induced under neuropathic conditions and mediate de novo methylation of the Kv1.2 gene.
Systemic paclitaxel administration in mice induced downregulation in the DRGs of K2p1.1, a member of the K2P family involved in the leak currents of neurons [32]. Evidence has been provided that K2p1.1 downregulation leads to increased neuronal excitability in DRG neurons and pain hypersensitivity. In DRG, paclitaxel treatment evoked an increased expression of DNMT3a but not DNMT3b or DNMT1. Finally, paclitaxel increased DNA methylation at the promoter region of the K2p1.1 gene. These data suggest that paclitaxel upregulates DNMT3a in DRG neurons, leading to enhanced methylation of the K2p1.1 promoter, resulting in K2p1.1 downregulation and neuronal excitation.

2.4.3. Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is released from central terminals of the nociceptive primary sensory neurons and contributes to spinal sensitization of the pain pathway. In rats with SNL, increased expression of TET1, peaking on day 7, was observed in the ipsilateral dorsal horn neurons [12]. As expected, SNL increased the global level of 5hmC in the ipsilateral dorsal horn, suggesting that SNL-increased spinal TET1 expression promotes DNA demethylation. SNL increased the conversion of 5mC to 5hmC at the CpG sites of the promoter of the BDNF gene. SNL increased the levels of BDNF in the dorsal horn, and this alteration was reduced by spinal TET1 knockdown. SNL-enhanced DNMT1, DNMT3a, and DNMT3b binding to the promoter of the BDNF gene were reduced on day 7 compared to day 3. TET1 knockdown increased DNMT1, DNMT3a, and DNMT3b binding to the promoter of the BDNF gene on day 7. These data indicate that, initially, methylation of the BDNF gene promoter is enhanced by DNMT enzymes, but later it is overcompensated by an increased spinal TET1 expression, partly by direct demethylation, partly by reducing DNMT binding. MeCP2 was shown to be upregulated in the SNI model of mice, and it was revealed that functional MeCP2 is needed for regular BDNF expression in DRG [33].

2.4.4. Other Proteins

The following epigenetic mechanism has been revealed regarding glutamic acid decarboxylase 67 (GAD67), an enzyme converting the main neuroexcitatory mediator glutamate to the main inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In rats with CCI, expression of DNMT3a, DNMT3b, and MeCP2 increased, whereas MBD2 expression decreased in the lumbar spinal cord [34]. These changes were associated with enhanced DNA methylation at the promoter of the GAD67 gene and downregulation of GAD67.
In rats with SNL, an upregulation of TET1 in the dorsal horn, but not the DRG, was found, which led to hypomethylation of the metabotropic glutamate receptor (mGlu) type 5 (mGlu5) gene promoter, causing increased expression of this receptor in the dorsal horn, with consequent mechanical allodynia and heat hyperalgesia [35]. It is worth mentioning that, in the same model, TET1 overexpression in the injured DRG (but not the spinal cord) by viral delivery of TET1 mRNA alleviated heat hyperalgesia and mechanical allodynia in rats [31].
The methylation levels of the genes of the metabotropic glutamate receptor type 4 (mGlu4), serotonin 5-HT4 receptor, β2 adrenergic receptor, and Kv5.1 channel were increased in both the CCI and SNL models of neuropathic pain in the rat [13]. Accordingly, the mRNAs of these receptors/channels were downregulated in the spinal cord. Intraperitoneally applied 5-azacytidine, a DNMT inhibitor, reversed the above-mentioned DNA and mRNA alterations and diminished neuropathic mechanical allodynia and heat hyperalgesia.
Regarding diabetic neuropathy, streptozotocin-induced diabetes attenuated the expression of DNMT3b, but not 3a, in the DRG, leading to demethylation at the promoter of the P2X3 purinoceptor gene [36]. This resulted in increased binding of p65, a subunit of the transcription factor nuclear factor kappa B (NF-κB), to the demethylated promoter region, which increased P2X3 channel expression in DRG neurons, contributing to mechanical allodynia. The nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3), a core inflammasome component, was upregulated in the DRGs of mice with streptozotocin-induced diabetes, and this latter alteration contributed to neuropathic mechanical allodynia [37]. The likely mechanism is the upregulation of TET2, leading to an increase in thioredoxin-interacting protein (TXNIP) expression in neurons, which can activate the NLRP3 inflammasome.
In various tumors, including oral squamous cell carcinoma, endothelin levels are increased. Endothelin acting at its type A receptors promotes nociception, whereas activation of type B receptors results in antinociception. In a human oral squamous cell carcinoma specimen, an elevated methylation level was detected at the promoter of the endothelin type B (ETB) receptor gene, along with reduced expression of ETB [38]. Restoring ETB receptor expression by a viral vector of the ETB gene in the tumor cells led to decreased endothelin secretion but increased beta-endorphin secretion. In a murine oral squamous cell carcinoma model, overexpression of the ETB receptor gene attenuated mechanical allodynia without affecting tumor size.
In oxaliplatin-treated rats, the transcription factor SRY-related HMG-box 10 (SOX10) was upregulated due to hypomethylation of the SOX10 gene promoter by upregulated TET1 [39]. Increased expression and binding of SOX10 to the promoter of the gene of the transcription factor homeobox A6 (HOXA6) protein led to HOXA6 upregulation in spinal dorsal horn neurons, which contributed to oxaliplatin-induced mechanical allodynia. Oxaliplatin-induced mechanical allodynia was shown to involve increased expression of the transcriptional regulator zinc-finger E-box-binding homeobox 1 (ZEB1) and the DNMT3b in the dorsal horn neurons of the rat [40]. Their enhanced interaction increased the methylation level at the promoter of the gene of the tyrosin kinase-linked receptor discoidin domain receptor type 1 (DDR1). This led to a decrease in DDR1 expression and mechanical allodynia.
In the intervertebral discs of mice, expression of secreted protein acidic and rich in cysteine (SPARC, also known as basement-membrane protein 40 or osteonectin) was shown to decrease with age, and this decline was associated with nociceptive responses resembling both axial and radicular low back pain of humans [41]. This age-dependent downregulation of SPARC was coupled with increased methylation of six CpG sites at the promoter of the SPARC gene. In addition, 5-azacytidine, a DNMT inhibitor, increased SPARC expression. In patients with chronic neuropathic pain, a correlation between transient receptor potential (TRP) ankyrin 1 (TRPA1) gene hypermethylation or TRPA1 mRNA downregulation in blood cells and pain score was established [42].

3. Histone Protein Modification by Acetylation/Deacetylation under Neuropathic Conditions

3.1. General Principles

The most extensively studied epigenetic modification to the histone proteins is acetylation occurring at lysine residues of the amino-terminal tail of histone molecules protruding from the nucleosomes [43][44]. This posttranslational alteration loosens the compact structure of the DNA, leading to the formation of euchromatin, thereby causing transcriptional activation. In addition, acetylated histone tails can serve as markers that attract various transcription factors, which is another method of transcriptional regulation. Histone acetyltransferase (HAT) enzymes confer an acetyl group onto the tail of the histone proteins. They can be classified as A-type HATs having numerous subtypes, including p300/CREB binding protein (CBP), general control non-derepressible 5 related acetyltransferases (GNAT), MYST, and other families, each comprising several isoforms and exerting histone acetylation in the nuclear chromatin. B-type HATs are located in the cytoplasm, and they acetylate de novo synthesized histone proteins, which are then transported to the nucleus. HAT isoenzymes exhibit different degrees of selectivity regarding target histones, with p300/CBP having the broadest substrate spectrum, as it can acetylate all types of histone subunits in the nucleosome. HAT inhibitors also possess different subtype selectivity, and they include, among others, curcumin, anacardic acid, and garcinol. Reader elements of this epigenetic machinery have also been identified. Bromodomain refers to an approximately 110 amino acid-long part of a protein, which can recognize acetylated lysine residues in histone or non-histone proteins. Bromodomain-containing proteins (such as bromodomain and extraterminal [BET] domain [BRD] proteins, including BRD2, BRD3, BRD4, and BRDT) are typical epigenetic readers possessing diverse functions, including HAT activity or direct transcriptional regulation.
Deacetylation of the histone tail induces compaction of the DNA, i.e., heterochromatin formation resulting in transcriptional repression. Histone deacetylase (HDAC) enzymes, being typical epigenetic erasers, remove the acetyl group from the histone tail, leading to heterochromatin formation. They are classified into four groups: Class I (including HDAC1, HDAC2, HDAC3, and HDAC8), class IIa (including HDAC4, HDAC5, HDAC7, and HDAC9), class IIb (including HDAC6 and HDAC10), and class IV (including HDAC11) enzymes, which hydrolyze the amide bond on the acetylated lysine residues using zinc ions as a cofactor. In contrast, class III HDAC enzymes, including silent information regulators (SIRT), so-called sirtuins (SIRT1–7), transfer the acetyl group from the acetylated lysine to nicotinamide adenine dinucleotide (NAD+). Most HDACs can be found either in the nucleus or in the cytoplasm. In contrast, class IIa HDACs shuttle between the nucleus and cytoplasm, which is regulated by phosphorylation at lysine residues. The phosphorylated form is extruded from the nucleus and, thus, remains in the cytoplasm. However, upon cytoplasmic dephosphorylation, it can be transported back to the nucleus. HDAC inhibitors, including sodium butyrate, trichostatin A, valproic acid, suberoylanilide hydroxamic acid (SAHA), etc., are also available similarly to SIRT inhibitors (nicotinamide, sirtinol, splitomicin). Interestingly, activators of SIRT enzymes such as resveratrol have also been identified. It must be emphasized that some HATs and HDACs can acetylate/deacetylate non-histone proteins, including NF-κB, making interpretation of the results obtained with HAT or HDAC inhibitors biased concerning epigenetic relevance.

3.2. Expression of Critical Elements of the Histone Acetylation Machinery in Nociceptive Primary Sensory Neurons

Expressions of HDAC1, HDAC2, HDAC4, and HDAC5 were revealed in rat DRG, with HDAC2, HDAC4, and HDAC5 being predominantly localized in neurons [45]. HDAC2, HDAC4, and HDAC5 were upregulated by SNL injury. HDAC2 expression has been revealed in dorsal horn neurons and, to a lesser extent, in astrocytes, but not in the microglia of rats [46]. Seven days following SNI, an increase in HDAC2 expression could be detected in spinal astrocytes but not neurons. In a rat model of bone cancer pain, HDAC1 was upregulated in neurons and astrocytes in the dorsal horn, while HDAC2 was upregulated in astrocytes [47]. In DRG, expression of both HDAC1 and HDAC2 was increased mainly in satellite glial cells. SIRT1 expression was revealed in spinal neurons but not glial cells [48].

3.3. Global Epigenetic Alterations Involving Histone Acetylation/Deacetylation in Animal Models of Neuropathic Pain

In the PSNL model of mice, the number of HDAC1-positive microglia in the ipsilateral dorsal horn was increased, and the acetylation of histone H3 at lysine (H3K) 9 residue (H3K9) in activated microglia was decreased [49]. These responses were reversed by treadmill running, along with a reduction of mechanical allodynia and heat hyperalgesia [49]. In rats with either PSNL or SNL (similarly to stavudine treatment), two different HDAC inhibitors (MS-275, MGCD0103) delivered intrathecally reduced nerve injury-induced mechanical and heat hyperalgesia, but only if HDAC inhibitor treatment preceded neuropathy induction [50]. The drugs increased global H3K9 acetylation in the spinal cord but not the DRG. In rats with SNL, increased HDAC1 expression and reduced H3 acetylation were measured in the dorsal horn [51]. Intrathecal treatment by the flavonoid baicalin reversed both of these changes, along with the diminishment of the tactile allodynia and heat hyperalgesia. In rats with CCI, sodium butyrate, an HDAC I and IIa inhibitor given orally for 14 days, diminished cold and mechanical allodynia, as well as heat and mechanical hyperalgesia [52]. In mice with SNL, mechanical allodynia was accompanied by cytoplasmic retention of HDAC4 in the ipsilateral dorsal horn neurons [53]. Nerve injury activated serum- and glucocorticoid-inducible kinase 1 (SGK1), which phosphorylates HDAC4 in the nucleus. Phosphorylated HDAC4 is exported from the nucleus to the cytoplasm, where it interacts with 14-3-3β, a phosphor-binding protein that acts as an anchoring element, which prevents its transport back to the nucleus. Cytoplasmic retention of HDAC4 prevents its ability to inhibit transcription in the nucleus, leading to possible upregulation of pronociceptive proteins.
In the SNI model of mice, HDAC1 and HDAC2 were upregulated in the spinal cord, but the expression level of HDAC3 remained unaltered [46][54][55][56]. The selective HDAC1 inhibitor LG325, applied intrathecally, reversed the upregulation of HDAC1 in the spinal cord and reduced mechanical allodynia [54]. Another HDAC1-selective inhibitor, zingiberene, given orally evoked the same effects and reduced heat hyperalgesia [56]. Combined inhibition of HDAC enzymes and BET proteins by intranasally applied inhibitors resulted in additive or even potentiating interactions in the SNI model, with a decrease in HDAC1, the reader protein BRD4 expression, microglia activation, spinal neuroinflammation, and mechanical allodynia, as well as heat hyperalgesia [57][58]. In the same model, nerve injury activated the mitogen-activated protein kinase C-Jun N-terminal kinase (JNK) 1 in the spinal cord [55]. JNK1 activation led to upregulation of HDAC1, which activates c-Jun. Direct evidence for the interaction between HDAC1 and c-Jun was also provided. However, in the SNI model of rats, a downregulation of HDAC1–3 was reported [4]. In mice with SNI, histone alterations (H3K4me1, H3K4me4, and H3K27ac) were examined in different brain areas related to pain [59]. In the periaqeductal grey matter, H3K4me1 levels were decreased. In the lateral hypothalamus H3K27ac levels were decreased. In the nucleus accumbens H3K27ac levels were also decreased. These chromatin alterations correlated with mechanical and thermal hypersensitivity caused by nerve injury.
As mentioned earlier, SIRT1 is a protein from the sirtuin family, a class III, NAD+-dependent HDAC. In rats or mice with CCI, heat hyperalgesia and mechanical allodynia were accompanied by SIRT1 downregulation in the spinal cord [60][61]. As expected, the H4 and H3 histone proteins exhibited an increased acetylation level. Intrathecally applied resveratrol, an activator of SIRT1, delayed the onset of hyperalgesia and allodynia, along with a reversal of histone hyperacetylation. Similar results have been obtained with SRT1720, a SIRT1 activator 1000 times more potent than resveratrol [62]. Inversely, a SIRT inhibitor prevented the antinociceptive actions of resveratrol. In rats with CCI, SRT1720 exerted antihyperalgesic/antiallodynic actions and decreased CCI-induced overexpression of the molecular target of rapamycin (mTOR), NF-κB, interleukin (IL) 6, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) [63]. CCI-induced upregulation of the protein factor erythroblast transformation specific (ETS) proto-oncogene I (ETSI) in small- and medium-sized DRG neurons was responsible for mechanical allodynia and heat hyperalgesia in mice [64]. ETSI was shown to induce HDAC1 upregulation through binding to its promoter, ultimately leading to an increased expression of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and glial fibrillary acidic protein (GFAP). Downregulation of SIRT1 in the spinal cord was also revealed in the paclitaxel-induced neuropathy model in the rat, similar to bortezomib-evoked neuropathy [65]. It was associated with H4 hyperacetylation and NF-kB (p65) phosphorylation.
In models of orofacial pain/trigeminal neuralgia in mice or rats, a global decrease in H3K9 acetylation was observed in injured trigeminal ganglion neurons, along with an alteration of the expression level of a huge array of genes [66][67]. Preemptive HDAC inhibition by either SAHA, MS-275, or carbamazepine restored H3K9ac levels and prevented mechanical allodynia. It was shown that the transfer of phosphate groups from activated extracellular signal-regulated kinase (ERK) and leucine-reach repeat kinase 2 onto HDAC3 causes hyperactivity of the enzyme in this type of neuropathy [67]. In rats with CCI in the infraorbital nerve, SIRT1 downregulation was revealed in GABAergic neurons of the central nucleus of the amygdala [68]. In accordance, in this area, a hyperacetylation of the H3K9 at the promoter of the Ca2+/calmodulin-dependent protein kinase IIaα (CaMKIIaα) gene was observed, along with an upregulation of the enzyme.

3.4. Proteins Regulated by Histone Acetylation/Deacetylation in Neuropathic Conditions

3.4.1. Neurotransmitters

Glutamate, the main excitatory neurotransmitter in the central nervous system, plays an important role in neurotransmission in the spinal dorsal horn, including central sensitization of the nociceptive transmission, thereby contributing to pain and hyperalgesia. GABA, the main inhibitory transmitter in the central nervous system, can counteract glutamate-mediated excitatory effects. Thus, the actual balance between the opposing glutamate-mediated and GABA-mediated synaptic activities determines the level of neural excitation in the spinal cord and brain.
In spinal neurons, but not glial cells, of type 2 diabetic rats, decreased expression and activity of SIRT1 was revealed [48]. This resulted in H3 hyperacetylation at the promoter region of the mGlu1/5 receptor genes, leading to increased expression of these receptors. In rats with SNL, expression of glutamic acid decarboxylase 65 (GAD65), an enzyme inactivating glutamate by converting it to GABA, was decreased in the nucleus raphe magnus of the brainstem, a critical site for the maintenance of hyperalgesia/allodynia [69]. Evidence has been provided that 3 weeks (but not 1 day) after injury, GAD65 downregulation was due to diminished H3 acetylation at the promoter region of the GAD65 gene. HDAC inhibitors restored the acetylation level and GABAergic neurotransmission in the nucleus raphe magnus neurons, attenuated by nerve injury and reversed neuropathic allodynia. In mice with SNI, GAD65 downregulation associated with an elevated glutamate/GABA ratio was revealed in the spinal cord [70]. HDAC inhibition restored this imbalance and attenuated mechanical allodynia. SNL induced downregulation of the glutamate transporter type 1 (GLT-1), together with HDAC2 upregulation and histone (H3K9) hypoacetylation in the dorsal horn of rats [71][72]. HDAC inhibition prevented all these alterations. HDAC2 upregulation depended on astrocytic activation (JNK phosphorylation) as an upstream event. Activated microglia contributed to this by increasing TNF-α secretion and consequent JNK phosphorylation in astrocytes. All the above data argue for an epigenetic regulation of the glutamate/GABA balance in the central nervous system by histone deacetylation.

3.4.2. Ion Channels and Transporters

Certain epigenetic mechanisms involve neuron-restrictive silencer factor (NRSF, also known as repressor element 1-silencing transcription factor, REST), which functions as a transcriptional repressor of genes that contain neuron-restrictive silencer element (NRSE, also called response element (RE) 1 [73]. NRSF is a zinc-finger DNA-binding protein, which, upon binding to NRSE, recruits various co-repressor factors such as mSin3 and co-repressor for REST. The formed co-repressor complexes modify target gene regions through HDACs, histone demethylase, etc., leading to a repressive chromatin conformation (heterochromatin). This repressive machinery can be stimulated by interaction with other epigenetic factors, including MeCP2 and Polycomb complexes.
In mice with PSNL, mRNA of Kv4.3 K+ channels that repress neuronal excitability was reduced in DRG neurons [74]. This alteration was associated with a decreased acetylation of H4, but not H3, protein at Kv4.3-NRSE and an increase in the binding of NRSF to Kv4.3-NRSE. The nerve injury-evoked Kv4.3 downregulation was reduced by antisense-knockdown of NRSF. These data suggest that nerve injury enhances NRSF binding and histone hypoacetylation at Kv4.3-NRSE, leading to Kv4.3 gene silencing. In the same model, a similar silencing effect, involving increased NRSF expression and binding as well as hypoacetylation at NRSE within the gene of the voltage-gated Na+ channel Nav1.8 in DRG neurons, was revealed [75][76]. NRSF knockdown blocked nerve injury-induced downregulation of not only Nav1.8, but also TRP melastatin 8 (TRPM8) and TRPA1 (though not calcitonin gene-related peptide [CGRP]) in DRG as well, together with C-fiber hypoesthesia, suggesting a role for epigenetic regulation of the negative signs of nerve injury. Interestingly, heat hyperalgesia and mechanical allodynia, underlying the positive signs of nerve injury, were not affected by NRSF knockdown. Various HDAC inhibitors (trichostatin A, valproic acid, and SAHA) restored nerve injury-induced downregulation of Nav1.8, TRPM8, and TRPA1 (but not CGRP) in DRG, together with the reversal of decreased C-fiber sensitivity. In addition, trichostatin A reversed the nerve injury-evoked hypoacetylation at H3-/H4-bound Nav1.8–NRSE. A similar transcriptional regulation has been revealed in the PSNL model of rats for Kv7.2/7.3 channels expressed in small-diameter DRG neurons, contributing to the hyperpolarizing M current: nerve injury-increased NRSF expression leads to suppression of the transcription of the Kv7.2/7.3 genes containing NRSE, which results in neuronal hyperexcitability [77][78].
In rats with CCI, HDAC2 was upregulated in DRG, along with decreased expression of Kv1.2 channels, co-localizing with HDAC2 in DRG neurons [79]. An intrathecally applied HDAC2 inhibitor or knockdown of HDAC2 by a small interfering RNA (siRNA) treatment reversed Kv1.2 downregulation and attenuated heat hyperalgesia and mechanical allodynia. These data indicate an epigenetic regulation by histone acetylation of Kv1.2 channels, contributing to pain hypersensitivity in this model.
In oxaliplatin-treated mice, an NRSF–HDAC3 pathway was revealed that leads to the downregulation of various K+ channels in DRG neurons, including two-pore channels such as TREK1 and TRAAK and voltage-gated ones such as Kv1.1 and Kv4.3; this mechanism is involved in the mechanical and cold hypersensitivity [80]. In the neuropathic model based on L5 ventral root transection, the mechanical allodynia was shown to involve upregulation of the Nav1.6 channel in DRG neurons [81]. This response was mediated by the TNF-α-phosphorylated transducer and activator of transcription-3 (pSTAT3)–p300 pathway in the sensory neurons, leading to hyperacetylation of H4, but not H3, histone at the promoter of the Nav1.6 gene.
In a rat model of bone cancer pain, HDAC2 was upregulated in the neurons and astroglia but not the microglia of the spinal cord [82]. In parallel, expression of the K+–Cl-cotransporter 2 (KCC2), responsible for maintaining low intracellular Cl levels, was reduced. Knockdown of HDAC2 restored the reduced expression of KCC2 and reduced mechanical allodynia, whereas trichostatin A suppressed HDAC2 overexpression and promoted H3 acetylation in the spinal cord. The mechanism of the reversal of HDAC upregulation by trichostatin A or other HDAC inhibitors is unclear. Very similar results were obtained in the CCI model of rats: HDAC2 was upregulated in neurons of the ipsilateral spinal cord; HDAC2 knockdown ameliorated mechanical allodynia and heat hyperalgesia, as well as providing increased expression of GAD65 and KCC2; and trichostatin A inhibited hypernociception and decreased elevated HDAC2 levels [83].

3.4.3. Opioid Receptors and Peptides

PSNL enhanced, in mice, NRSF binding to MOP–NRSE in DRG neurons, which reduced MOP receptor gene expression through HDAC recruitment [75]. NRSF knockdown restored both MOP receptor downregulation and morphine antinociception (inhibition of heat hyperalgesia and mechanical allodynia) diminished by nerve injury. In accord, HDAC inhibitors (trichostatin A, valproic acid) restored both the downregulation of MOP receptors and the diminished morphine analgesia upon systemic or local administration [84]. In a model of bone cancer pain in rats, mechanical allodynia was associated with reduced MOP receptor expression in the spinal cord [85]. The nonselective HDAC inhibitor trichostatin A partially reversed both phenomena and potentiated the antinociceptive effect of morphine. In the same model, HDAC1 and 2 proteins were upregulated in DRG, along with the downregulation of MOP receptors [86]. SAHA reduced HDAC expression and increased MOP receptor expression, thereby counteracting morphine tolerance. However, in another study using the same model, the knockdown of HDAC2 failed to restore reduced MOP receptor density [82]. In mice with CCI, HDAC1 upregulation was revealed in the injured DRG, and HDAC1 was shown to bind to the promoter region of the MOP receptor gene [28]. Furthermore, SAHA restored MOP receptor downregulation in DRG and the reduced antinociceptive efficacy of morphine; as well, it prevented the hypoacetylation of the H3 protein.
In rats with CCI to the infraorbital nerve, reduced β-endorphin expression was observed in the hypothalamic arcuate nucleus, along with mechanical allodynia [87]. It has been shown that nerve injury downregulates HDAC9, leading to hyperacetylation (H3K18ac enrichment) of the micro RNA miR-203a-3p gene promoter. This enhances the binding of the transcription factor NR4A2 to the promoter, thereby facilitating miR-203a-3p expression. Upregulated miR-203a-3p reduces the expression of proprotein convertase 1, responsible for the generation of β-endorphin from its precursor proopiomelanocortin.


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