The Epigenetics of Neuropathic Pain: A Systematic Update
Abstract
:1. Basic Concepts of Epigenetics
2. The Role of DNA Methylation/Demethylation in Neuropathic Pain
2.1. General Principles
2.2. Expression of Elements of the DNA Methylation Machinery in Primary Sensory Neurons
2.3. Global Changes in DNA Methylation under Neuropathic Conditions
2.4. Proteins Regulated by DNA Methylation in Neuropathic Conditions
2.4.1. Opioid Receptors
2.4.2. K+ Channels (Kv1.2, K2p1.1)
2.4.3. Brain-Derived Neurotrophic Factor
2.4.4. Other Proteins
3. Histone Protein Modification by Acetylation/Deacetylation under Neuropathic Conditions
3.1. General Principles
3.2. Expression of Critical Elements of the Histone Acetylation Machinery in Nociceptive Primary Sensory Neurons
3.3. Global Epigenetic Alterations Involving Histone Acetylation/Deacetylation in Animal Models of Neuropathic Pain
3.4. Proteins Regulated by Histone Acetylation/Deacetylation in Neuropathic Conditions
3.4.1. Neurotransmitters
3.4.2. Ion Channels and Transporters
3.4.3. Opioid Receptors and Peptides
3.4.4. Cytokines, Chemokines, and Growth Factors
3.4.5. Inflammasome Proteins
3.4.6. Other Proteins
4. Histone Protein Modification by Methylation/Demethylation in Neuropathic Conditions
4.1. General Principles
4.2. Proteins Regulated by Histone Methylation/Demethylation
4.2.1. K+ Channels
4.2.2. Opioid Receptors
4.2.3. Other Proteins
5. Epigenetic Regulation of the Baseline Noxious Mechanical or Heat Threshold
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
Abbreviations
5mC | 5-methylcytosine |
5hmC | 5-hydroxymethylcytosine |
AMP | adenosine monophosphate |
AMPK | AMP-activated kinase |
BDNF | brain-derived neurotrophic factor |
BET | bromodomain and extraterminal |
BRD | bromodomain-containing proteins |
CaMKIIaα | Ca2+/calmodulin-dependent protein kinase IIaα |
CARM | coactivator-associated arginine methyltransferase |
CBP | CREB binding protein |
CCI | chronic constriction injury |
CCL | C-C motif chemokine ligand |
CCR | C-C motif chemokine receptor |
Cdk5 | cyclin-dependent kinase 5 |
CXCR | chemokine CC motif receptor |
CGRP | calcitonin gene-related peptide |
COX-2 | cyclooxygenase 2 |
CREB | cyclic AMP-response element binding protein |
CX3CL | chemokine C-X3-C motif ligand |
CXCL | C-X-C motif ligand |
DDR1 | discoidin domain receptor type 1 |
DNA | deoxyribonucleic acid |
DNMT | DNA methyltransferase |
DOP | delta opioid receptor |
DRG | dorsal root ganglia |
ERK | extracellular signal-regulated kinase |
ETB | endothelin type B |
ETS | erythroblast transformation specific |
ETSI | erythroblast transformation specific proto-oncogene I |
EZH2 | enhancer of the histone methyltransferase zeste homolog-2 |
GABA | gamma-aminobutyric acid |
GAD65 | glutamic acid decarboxylase 65 |
GAD67 | glutamic acid decarboxylase 67 |
GFAP | glial fibrillary acidic protein |
GLP | G9a-like protein |
GLT-1 | glutamate transporter type 1 |
GNAT | general control non-derepressible 5-related acetyltransferases |
H3K | histone H3 at lysine |
H3K9 | histone H3 at lysine 9 |
H3K9me2 | dimethylation of histone H3 at lysine 9 |
H3K27me3 | trimethylation of histone H3 at lysine 27 |
H4K | histone H4 at lysine |
HAT | histone acetyltransferase |
HDAC | histone deacetylase |
HDM | histone demethylase |
HMGB | high-mobility group box |
HMT | histone methyltransferase |
HOXA6 | homeobox A6 |
IL | interleukin |
iNOS | inducible nitric oxide synthase |
JMJD | jumonji domain-containing protein |
JNK1 | C-Jun N-terminal kinase 1 |
K2P | two-pore-domain K+ channel |
KCC2 | K+–Cl−-cotransporter 2 |
KDM | lysine demethylase enzyme |
KOP | kappa opioid receptor |
MBD | methyl-CpG-binding domain |
MCP | monocyte chemotactic protein |
MeCP2 | methyl-CpG-binding protein 2 |
mGlu | metabotropic glutamate receptor |
MIF | macrophage migration inhibiting factor |
MIP | macrophage inflammatory protein |
MLL1 | mixed lineage leukemia type 1 |
MOP | mu opioid receptor |
mTOR | molecular target of rapamycin |
NAD+ | nicotinamide adenine dinucleotide |
NALP | NACHT leucine-rich-repeat protein |
NFATc2 | nuclear factor of activated T cells type 2 |
NF-κB | nuclear factor kappa B |
NGF | nerve growth factor |
NEK | NIMA-related kinase |
NLRP3 | nucleotide oligomerization domain-like receptor protein 3 |
NMDA | N-methyl-D-aspartate |
NOD | nucleotide oligomerization domain |
NRSF | neuron-restrictive silencer factor |
NRSE | neuron-restrictive silencer element |
OCT1 | octamer transcription factor 1 |
PADI | peptidyl arginine deiminase |
pERK1/2 | phosphorylated extracellular signal-regulated kinase 1 and 2 |
PGC-1α | peroxisome proliferator-activated receptor-γ coactivator-1α |
PKA | protein kinase A |
PKC | protein kinase C |
PPAR | peroxisome proliferator-activated receptor |
pRSK2 | phosphorylated p90 ribosomal S6 kinase 2 |
PRMT | protein arginine methyltransferase |
PSNL | partial sciatic nerve ligation |
pSTAT3 | phosphorylated transducer and activator of transcription-3 |
RE | response element |
REST | repressor element 1-silencing transcription factor |
RNA | ribonucleic acid |
mRNA | messenger ribonucleic acid |
SAHA | suberoylanilide hydroxamic acid |
SETDB1 | SET domain bifurcated histone lysine methyltransferase 1 |
SGK1 | serum- and glucocorticoid-inducible kinase 1 |
shRNA | short hairpin ribonucleic acid |
siRNA | small interfering ribonucleic acid |
SIRT | silent information regulator |
SNI | spared nerve injury |
SNL | spinal nerve ligation |
Sp1 | specificity protein 1 |
SPARC | secreted protein acidic rich in cysteine |
SOX10 | SRY-related HMG-box 10 |
STAT | signal transducer and activator |
SUV39H1 | suppressor of variegation 3-9 homolog 1 |
TET | ten-eleven translocation |
TLR4 | toll-like receptor 4 |
TNF-α | tumor necrosis factor α |
TRP | transient receptor potential |
TRPA1 | transient receptor potential ankyrin 1 |
TRPM8 | transient receptor potential melastatin 8 |
TRPV1 | transient receptor potential vanilloid 1 |
TSC2 | tuberous sclerosis complex protein 2 |
TXNIP | thioredoxin-interacting protein |
VEGF | vascular endothelial growth factor |
VEGFR | vascular endothelial growth factor receptor |
WDR5 | WD repeat-containing protein 5 |
ZEB1 | zinc-finger E-box-binding homeobox 1 |
ZNF | zinc-finger protein |
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Neuropathy Model | Species | Epigenetic Alteration(s) | Epigenetically Regulated Change(s) in Gene Expression | Epigenetically Regulated Nociceptive Response(s) | Reference(s) |
---|---|---|---|---|---|
Chronic constriction injury (CCI) | Male Sprague–Dawley rats | Global DNA hypermethylation, MeCP2 mRNA, and nuclear MeCP2 protein upregulation in the spinal cord | – | Mechanical allodynia, heat hyperalgesia | [9] |
Male C57BL/6J mice | Hypermethylation of the MOP gene proximal promoter | MOP downregulation in DRG and spinal cord | Heat hyperalgesia | [27] | |
Male C57BL/6J mice | Hypermethylation + increased MeCP2 binding at the MOP gene promoter | MOP downregulation in DRG neurons | Heat hyperalgesia | [28] | |
Male C57BL/6J mice | DNMT3a expression ↑ → methylation of MOP gene promoter ↑ | MOP downregulation in the spinal cord | Heat hyperalgesia | [30] | |
Male Sprague–Dawley rats | OCT1 upregulation → DNMT3a upregulation | MOP and Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia, cold allodynia | [29] | |
Male C57BL/6J mice | CREB upregulation → DNMT1 upregulation | Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia, cold allodynia | [7] | |
Male Sprague–Dawley rats | DNMT3a, 3b, MeCP2 upregulation → hypermethylation at the promoter of the GAD67 gene | GAD67 mRNA downregulation in the spinal cord | Mechanical allodynia | [34] | |
Male Sprague–Dawley rats | Hypermethylation of the mGlu4, 5-HT4, β2, Kv5.1 genes | mGlu4, 5-HT4, β2, Kv5.1 mRNA decrease in the spinal cord | Mechanical allodynia, heat hyperalgesia | [13] | |
Spinal nerve ligation (SNL) | Male Sprague–Dawley rats; C57B/L6 mice | DNMT3a upregulation → hypermethylation of the MOP gene promoter + increased MBD1 binding | MOP and KOP downregulation in DRG | Heat hyperalgesia | [5] |
Male Sprague–Dawley rats | OCT1 upregulation → DNMT3a upregulation → hypermethylation at the Kv1.2 gene promoter | Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat, and cold hyperalgesia | [6] | |
Male C57BL/6J mice | CREB upregulation → DNMT1 upregulation | Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia, cold allodynia | [7] | |
Male C57BL/6J mice | MBD1 upregulation → DNMT3a binding to MOP and Kv1.2 gene promoter ↑ | MOP and Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia, cold allodynia | [10] | |
Male Sprague–Dawley rats | DNA hypermethylation at the promoters of the MOP and Kv1.2 genes | MOP and Kv1.2 downregulation in DRG | Mechanical allodynia, heat hyperalgesia | [31] | |
Male Sprague–Dawley rats | TET1 upregulation, TET1–mGlu5 coupling → demethylation of the mGlu5 gene promoter ↑ | mGlu5 upregulation in the dorsal horn | Mechanical allodynia, heat hyperalgesia | [35] | |
Male Sprague–Dawley rats | DNMT1, 3a, 3b binding to the BDNF gene promoter ↑, methylation ↑, later TET1 upregulation → demethylation at the CpG sites of the BDNF gene promoter | BDNF upregulation in the dorsal horn | Mechanical allodynia | [12] | |
Male Sprague–Dawley rats | CpG hypomethylation in DRG → hypermethylation in the spinal cord and prefrontal cortex | 1684 genes are upregulated, 1039 genes are downregulated in DRG | Mechanical allodynia | [15] | |
Male Sprague–Dawley rats | Hypermethylation of the mGlu4, 5-HT4, β2, Kv5.1 genes | mGlu4, 5-HT4, β2, Kv5.1 mRNA decrease in the spinal cord | Mechanical allodynia, heat hyperalgesia | [13] | |
Spared nerve injury (SNI) | Male CD1 mice | Global DNA hypomethylation in the prefrontal cortex | – | Mechanical allodynia, cold hyperalgesia | [17] |
Male Sprague–Dawley rats | Global DNA hypomethylation in the prefrontal cortex | – | Mechanical allodynia | [18] | |
Male Sprague–Dawley rats | TET1 expression in the prefrontal cortex ↑ | – | – | [22] | |
Male Sprague–Dawley rats | DNMT1 expression in the hippocampus ↑ | – | – | [21] | |
Male Sprague–Dawley rats | mRNAs of DNMT1, 3a, 3b and MeCP2 ↓ in the dorsal horn | – | – | [4] | |
Male C57BL/6J mice | TET3 mRNA ↑ → DNA hypomethylation in DRG neurons | – | – | [11] | |
Male C57BL/6J mice | MeCP2 upregulation in DRG | BDNF upregulation in DRG | Mechanical allodynia, heat hyperalgesia | [33] | |
Partial sciatic nerve ligation (PSNL) | Male C57BL/6J mice | Global DNA hypomethylation in the prefrontal cortex + DNMT1, 3a, 3b expression ↓ | – | Mechanical allodynia, cold allodynia | [23] |
Axotomy | Male C57BL/6J mice | CREB upregulation → DNMT1 upregulation | Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia, cold allodynia | [7] |
Tibial nerve transection | Male C57BL/6 mice | Global DNA hypermethylation in the primary somatosensory cortex | – | – | [24] |
Cancer pain | Human cancer specimen + female BALB/c mice | Hypermethylation at the promoter of the ETB gene | Downregulation of the ETB mRNA | Mechanical allodynia | [38] |
Male Copenhagen rats | DNMT3a upregulation | Kv1.2 downregulation in the dorsal horn | Mechanical allodynia, heat hyperalgesia, cold allodynia | [8] | |
Cancer chemotherapy-induced neuropathic pain | Male CD1 mice | Paclitaxel-induced DNMT3a upregulation and binding → hypermethylation at the K2p1.1 promoter | K2p1.1 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [32] |
Male Sprague–Dawley rats | Oxaliplatin-induced TET1 upregulation → demethylation of the SOX10 gene promoter | SOX10 upregulation → HOXA6 upregulation in dorsal horn neurons | Mechanical allodynia | [39] | |
Male Sprague–Dawley rats (oxaliplatin) | ZEB1, DNMT3b upregulation → hypermethylation at the promoter of the DDR1 gene | DDR1 downregulation in the dorsal horn neurons | Mechanical allodynia | [40] | |
Diabetic neuropathy | Female Sprague–Dawley rats | DNMT3b downregulation in DRG → hypomethylation of CpG sites at the promoter of the P2X3 gene | P2X3 upregulation in DRG | Mechanical allodynia, heat hyperalgesia | [36] |
C57BL/6 mice | TET2 upregulation → hypomethylation in the TXNIP gene | TXNIP upregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [37] | |
Chronic low back pain | Female C57BL/6J mice + Humans | Hypermethylation of the SPARC gene promoter | Downregulation of SPARC in intervertebral discs | Increased axial pain | [41] |
Chronic pain | Patients | DNA hypermethylation at the CpG island of the TRPA1 gene | TRPA1 mRNA in blood cells ↓ | DN4 questionnaire score ↑ | [42] |
Neuropathy Model | Species | Epigenetic Alteration(s) | Epigenetically Regulated Change(s) in Gene Expression | Epigenetically Regulated Nociceptive Response(s) | Reference(s) |
---|---|---|---|---|---|
Partial sciatic nerve ligation (PSNL) | Male Wistar rats | Histone acetylation in H3K9 promoters ↓ in spinal cord | – | Mechanical allodynia, heat hyperalgesia | [50] |
Male C57BL/6J mice | H4 acetylation at Kv4.3-NRSE ↓ | Kv4.3 mRNA in DRG ↓ | – | [74] | |
Male C57BL/6J mice | H3/H4 hypoacetylation at NRSEs within MOP and Nav1.8 genes ↓ | NRSF upregulation in DRG → MOP, Nav1.8, TRPM8, TRPA1 expression in the DRG ↓ | Tactile allodynia, heat hyperalgesia | [75,84] | |
Male ICR mice | H3 hyperacetylation at the MIP-2 and CXCR2 promoter in the sciatic nerve | Upregulation of MIP-2, CXCR2, IL-1β, TNF-α, MIP-1α, MIP-1β in neutrophils, macrophages | Tactile allodynia, heat hyperalgesia | [88] | |
Male ICR mice | H3 hyperacetylation at the CCL2 and CCL3 gene promoters in the sciatic nerve | mRNA of CCL2, CCL3, CCR2, CCR1/5 ↑ in macrophages | – | [89] | |
Male IRC mice | H3 hyperacetylation at the VEGF gene promoter in the sciatic nerve | VEGFA upregulation in macrophages, neutrophils | – | [90] | |
Male C57BL/6J mice | H3 and H4 hyperacetylation at BDNF gene promoter | BDNF upregulation in the dorsal horn | – | [91] | |
Male C57BL/6J mice | HDAC1 upregulation, H3K9 hypoacetylation in microglia of the dorsal horn | – | – | [49] | |
Male Wistar rats | REST upregulation in DRG | Kv7.2, Kv 7.3 mRNA downregulation in DRG | Mechanical allodynia, heat hyperalgesia | [77,78] | |
Male C57BL/6J mice | HDAC5 upregulation at the promoter of the SOX10 gene | SOX10 upregulation in dorsal horn neurons | Mechanical allodynia, heat hyperalgesia | [102] | |
Male C57BL/6J mice | H3 and H4 hypoacetylation at Nav1.8–NRSE | Nav1.8 mRNA ↓ TRPA1 mRNA ↓ TRPM8 mRNA ↓ in DRG | C-fiber hypoesthesia | [76] | |
Chronic constriction injury (CCI) | Male Sprague–Dawley rats | p300 upregulation and recruitment to the COX-2 gene promoter | COX-2 upregulation in the dorsal horn | Mechanical allodynia, heat hyperalgesia | [100] |
Male Sprague–Dawley rats | SIRT1 downregulation → H3 hyperacetylation in the spinal cord | – | Mechanical allodynia, heat hyperalgesia | [60] | |
Male Kunming mice | SIRT1 downregulation → H4 hyperacetylation in the spinal cord | – | Mechanical allodynia, heat hyperalgesia | [61] | |
Male Sprague–Dawley rats | HDAC overactivity | Upregulation of mTOR, NF-κB, IL-6, TNF-α, iNOS | Mechanical allodynia, heat hyperalgesia | [63] | |
Male Sprague–Dawley rats | phosphorylated CREB → H4 hyperacetylation at the Cdk5 gene promoter | Cdk5 mRNA ↑ in the dorsal horn | Mechanical allodynia, heat hyperalgesia | [101] | |
Male Sprague–Dawley rats | HDAC2 upregulation | Downregulation of GAD65 and KCC2 in the spinal cord | Mechanical allodynia, heat hyperalgesia | [83] | |
Male Sprague–Dawley rats | HDAC2 upregulation | Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [79] | |
Male C57BL/6 mice | HDAC1 upregulation, reduced H3 acetylation at the MOP gene promoter in DRG | Decreased MOP expression in the DRG | Heat hyperalgesia | [28] | |
Male C57BL/6J mice | H3 hyperacetylation at the CXCL13 promoter | CXCL13 upregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [95] | |
Sprague–Dawley rats | Sp1 ↑ → HDAC2 binding to PGC-1α gene promoter | PGC-1α downregulation in the spinal cord | Mechanical allodynia, heat hyperalgesia | [104] | |
Male KM mice | ETSI ↑ → HDAC1 upregulation in DRG neurons | – | Mechanical allodynia, heat hyperalgesia | [64] | |
Spinal nerve ligation (SNL) | Male Wistar rats | Histone acetylation in H3K9 promoters ↓ in spinal cord | – | Mechanical allodynia, heat hyperalgesia | [50] |
Male Wistar rats | HDAC1 upregulation, H3 hypoacetylation in the dorsal horn | – | Mechanical allodynia, heat hyperalgesia | [51] | |
Male Wistar rats | H3 hypoacetylation at the promoter of GAD65 gene | GAD65 downregulation in the nucleus raphe magnus | Mechanical allodynia | [69] | |
Male Sprague–Dawley rats | Hypoacetylation of H3K9 | GLT-1 downregulation in the dorsal horn | Mechanical allodynia, heat hyperalgesia | [71] | |
Male Sprague–Dawley rats | TNF-α + phosphorylated JNK → HDAC2 upregulation | GLT-1 downregulation in the dorsal horn | Mechanical allodynia | [72] | |
Male C57BL/6J mice | H3 hyperacetylation at the CXCL13 promoter | CXCL13 upregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [95] | |
Male C57BL/6J mice | Sp1 ↑ → HDAC1 upregulation and binding to the SOX10 gene promoter | SOX10 upregulation in the dorsal horn | Mechanical allodynia, heat hyperalgesia | [103] | |
Male Sprague–Dawley rats | HDAC2 occupancy at the α2δ-1 gene promoter ↓ → hyperacetylation | α2δ-1 upregulation in the DRG | Mechanical allodynia | [105] | |
Male Sprague–Dawley rats | HDAC4 retention in the cytoplasm | – | – | [53] | |
Spared nerve injury (SNI) | Male CD1 mice | HDAC1, BRD4 upregulation in the spinal cord | – | Mechanical allodynia, heat hyperalgesia | [54,57,58] |
Male CD1 mice | HDAC1 upregulation in the spinal microglia | – | Mechanical allodynia, heat hyperalgesia | [56] | |
Male CD1 mice | HDAC1 upregulation in the spinal cord | Mechanical allodynia | [55] | ||
Male Sprague–Dawley rats | HDAC1–3 downregulation in the spinal cord | – | – | [4] | |
Male and female C57BL/6J mice | H3K27ac ↓ in the lateral hypothalamus and nucleus accumbens | – | Mechanical allodynia, thermal hyperalgesia | [59] | |
Male C57BL/6J mice | H3 hyperacetylation at the CXCL13 promoter | CXCL13 upregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [95] | |
Male C57BL/6 mice | HDAC overactivity | GAD65 downregulation in the spinal cord | Mechanical allodynia | [70] | |
Bone cancer pain | Female Wistar rats, female Sprague–Dawley rats | HDAC2 upregulation in spinal neurons and astroglia | Downregulation of KCC2 in the spinal cord | Mechanical allodynia | [82] |
Female Wistar or Sprague–Dawley rats | HDAC1 and HDAC2 upregulation in the DRG | MOP downregulation in the spinal cord | Mechanical allodynia, heat hyperalgesia | [85,86] | |
Female Sprague–Dawley rats | HDAC1 and HDAC2 upregulation in the DRG | Glycogen synthase kinase 3β, TNF-α, IL-1β, IL-6 in DRG ↑ | Mechanical allodynia | [47] | |
Cancer chemotherapy-induced neuropathic pain | Male Sprague–Dawley rats | Paclitaxel-induced, NF-κB-dependent H4 hyperacetylation at the promoter of the CX3CL1 gene | CX3CL1 upregulation in spinal neurons | Mechanical allodynia | [93] |
Male Sprague–Dawley rats, male C57BL/6 mice | pSTAT3- and p300-dependent H4 hyperacetylation at the promoter of the CXCL12 gene | CXCL12 upregulation in dorsal horn neurons | Mechanical allodynia | [94] | |
Male C57BL/6J mice | Oxaliplatin-induced upregulation of the NRSF–NRSE–HDAC3 pathway | Downregulation of TREK1, TRAAK, Kv1.1, and Kv4.3 in DRG | Mechanical and cold allodynia | [80] | |
Male Sprague–Dawley rats | Oxaliplatin-induced H4 hypoacetylation at the promoter of the TSC2 gene | Downregulation of TSC2 in the dorsal horn | Mechanical allodynia | [107] | |
Bortezomib-induced neuropathy | Male Sprague–Dawley rats, C57BL/6 mice | STAT3 ↑ → global acetylation of H3 and H4 ↑, hyperacetylation at the NLRP3 gene promoter | NLRP3 upregulation in the DRG | Mechanical allodynia | [99] |
Male Sprague–Dawley rats, C57BL/6 mice | SIRT1 downregulation → pSTAT3 → p-STAT3–p300 interaction → H3 and H4 hyperacetylation at the NALP1 gene promoter | NALP1 upregulation in the dorsal horn | Mechanical allodynia | [62] | |
Male Sprague–Dawley rats | SIRT1 downregulation H4 hyperacetylation in the spinal cord | TNFα, IL-1β, IL-6 ↑, NF-κB phosphorylation | Mechanical allodynia | [65] | |
Male Sprague–Dawley rats | H3 hypoacetylation at the AMPKa2 gene promoter | AMPKa2 downregulation in the dorsal horn | – | [106] | |
Stavudine-induced neuropathy | Male Wistar rats | Histone acetylation in H3K9 promoters ↓ in spinal cord | – | Mechanical allodynia, heat hyperalgesia | [50] |
Diabetic neuropathy | Male Sprague–Dawley rats | SIRT1 downregulation → H3 hyperacetylation at the mGlu1/5 gene promoters | mGlu1/5 upregulation in spinal neurons | Mechanical allodynia, heat hyperalgesia | [48] |
Zucker diabetic (Type 2) fatty rats | Hperacetylation (H3K9) at the HMGB1 gene promoter | HMGB1 upregulation in the spinal cord and DRG | Mechanical allodynia, heat hyperalgesia | [96] | |
L5 ventral root transection | Male Sprague–Dawley rats, C57BL/6 mice | TNF-α–pSTAT3–p300 → H4 hyperacetylation at the Nav1.6 gene promoter | Nav1.6 upregulation in the DRG | Mechanical allodynia | [81] |
Brachial plexus avulsion | Male Sprague–Dawley rats | HDAC activation, Akt-H3K9, Ac-H4K12 in DRG ↓ | TNF-α, IL-1β, IL-6, TRPV1, TRPM8 in DRG ↑ | Mechanical allodynia | [97] |
Spinal cord injury | C57BL/6 mice | Histone hyperacetylation | TNF-α, IL-1β, IL-6 upregulation; IL-4, IL-10, IL-13 downregulation in the spinal cord | Mechanical allodynia | [98] |
Trigeminal neuralgia | Female Sprague–Dawley rats | H3K9 acetylation in the trigeminal ganglion ↓ | – | Mechanical allodynia | [67] |
Trigeminal inflammatory compression | Male BALB/C mice | H3K9 acetylation in the trigeminal ganglion ↓ | – | Whisker pad mechanical hypersensitivity | [66] |
Chronic constriction injury (CCI) to the infraorbital nerve | Male Wistar rats | SIRT1 downregulation → H3K9ac ↑ at the promoter of the CaMKIIaα gene | CaMKIIaα downregulation in the central nucleus of the amygdala | – | [68] |
Male and female Sprague–Dawley rats | HDAC9 downregulation → H3K18ac ↑ at the promoter of the miR-203a-3p gene | miR-203a-3p → proprotein convertase 1 expression ↓ → β-endorphin downregulation in the hypothalamic arcuate nucleus | Mechanical allodynia | [87] |
Neuropathy Model | Species | Epigenetic Alteration(s) | Epigenetically Regulated Change(s) in Gene Expression | Epigenetically Regulated Nociceptive Response(s) | Reference(s) |
---|---|---|---|---|---|
Chronic constriction injury (CCI) | Male C57BL/6J mice | MIF upregulation → G9a, SUV39H1 upregulation → H3K9me2/3 enrichment → increased CpG island methylation at the promoter of the tyrosine hydroxylase gene | Downregulation of tyrosine hydroxylase and dopamine in the ventral tegmental area | Mechanical allodynia, heat hyperalgesia | [119] |
Male C57BL/6J mice | CARM1 upregulation in DRG neurons | – | Mechanical allodynia, heat hyperalgesia | [109] | |
Male Wistar rats | CGRP upregulation → EZH2 up-regulation, and H3K27me3 enrichment in microglia | Upregulation of several microglial activation markers | Mechanical allodynia, heat hyperalgesia | [115] | |
Spinal nerve ligation (SNL) | Male Sprague–Dawley rats | G9a upregulation → increased H3K9me2 occupancy at the promoters of Kv1.4, Kv4.2, Kv7.2, and Ca2+-activated K+ channel genes | Kv1.4, Kv4.2, Kv7.2, and Ca2+-activated K+ channel mRNA levels decrease in DRG neurons | Tactile allodynia, mechanical hyperalgesia | [45] |
Male C57BL/6J mice | G9a upregulation → increased H3K9me2 level | Kv1.2 downregulation in DRG neurons | Mechanical allodynia, heat, and cold hyperalgesia | [110] | |
Male Sprague–Dawley rats | Increased H3K9me2 level at the promoter of the MOP gene | MOP downregulation in the DRG | Mechanical allodynia | [113] | |
C54BL/6J mice, Sprague–Dawley rats | Increase in G9a and H3K9me2 in the MOP, DOP, and KOP genes | MOP, DOP, KOP downregulation in the DRG | Mechanical allodynia, heat hyperalgesia | [112] | |
Male C57BL/6J mice | CARM1 upregulation in DRG neurons | – | Mechanical allodynia, heat hyperalgesia | [109] | |
Male and female Sprague–Dawley rats | CARM1 downregulation, H3R17me2 decrease at the promoter of the Kv1.4 and Kv4.2 genes | Kv1.4 and Kv4.2 downregulation in dorsal horn neurons | Mechanical allodynia | [111] | |
Male Sprague–Dawley rats | KDM6B upregulation → H3K27me3 demethylation at the promoter of the IL-6 gene | IL-6 upregulation in the DRG and dorsal horn | Mechanical allodynia, heat hyperalgesia | [121] | |
Male Sprague–Dawley rats | MLL1 upregulation and interaction with WDR5 → H3K4me3 enrichment at the promoter of the mGlu5 gene | mGlu5 upregulation in dorsal horn neurons | Mechanical allodynia | [125] | |
Male Sprague–Dawley rats | Enrichment of H3K4me3, H3K9ac, reduction in H3K9me2, H3K27me3 at the promoter of the CB2 receptor gene | CB2 receptor upregulation in the DRG | – | [122] | |
Spared nerve injury (SNI) | Male and female C57BL/6J mice | H3K4me1 ↓ in the periaqueductal grey matter | – | Mechanical allodynia, thermal hyperalgesia | [59] |
Male C57BL/6J mice | G9a/GLP upregulation, increased DNA methylation in the tyrosine hydroxylase gene | Downregulation of tyrosine hydroxylase and dopamine in the ventral tegmental area | Mechanical allodynia | [118] | |
Male Sprague–Dawley rats | MLL1 upregulation and interaction with WDR5 → H3K4me3 enrichment at the promoter of the mGlu5 gene | mGlu5 upregulation in dorsal horn neurons | Mechanical allodynia | [125] | |
Partial sciatic nerve ligation (PSNL) | Male Sprague–Dawley rats | EZH2 and H3K27me3 upregulation in dorsal horn neurons and microglia | – | Mechanical allodynia, heat hyperalgesia | [114] |
Male C57BL/6J mice | IL-6 → pSTAT3 and PU.1 upregulation → decreased enrichment of H3K27me3 at the promoter of the MCP-3/CCL7 gene | MCP-3/CCL7 upregulation in spinal astrocytes | Mechanical allodynia, heat hyperalgesia | [126] | |
Cancer chemotherapy-induced neuropathic pain | Male C57BL/6J mice | Cisplatin-induced decrease in H3.1K27me and H3K56me3 enrichment in microglia | – | Mechanical allodynia | [116] |
Male and female Sprague–Dawley rats | Paclitaxel-induced pNEK2 upregulation → KDM6 upregulation → demethylation of H3K27me3 at the promoter of the TRPV1 gene | TRPV1 upregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [123] | |
Male and female Sprague–Dawley rats | Paclitaxel-induced NAD+ phosphate oxidase 4 → PRMT5 upregulation → H3R2me2 enrichment then WDR5-mediated H3K4me3 enrichment at the TRPV1 gene promoter | TRPV1 upregulation in DRG neurons | Mechanical allodynia, heat hyperalgesia | [124] | |
Bortezomib-induced neuropathy | Male C57BL/6J mice | Prokineticins → KDM6A upregulation in the spinal cord | – | Mechanical allodynia | [117] |
Enzyme | Inhibitor | Model(s) | Reference(s) |
---|---|---|---|
DNA methyltransferase (DNMT) | 5-Azacytidine | CCI/SNL/Chronic low back pain | [9,13,41] |
5-Aza-deoxycytidine | CCI | [27,28] | |
Decitabine | Bone cancer | [8] | |
RG108 | CCI/SNL | [15,30] | |
Histone deacetylase (HDAC) | MS275 | SNL/PSNL/Stavudine-induced neuropathy/Trigeminal inflammatory compression/SNI | [50,66,70] |
MGCD0103 | SNL, PSNL, Stavudine-induced neuropathy | [50] | |
Baicalin | SNL | [51] | |
Sodium butyrate | CCI | [52] | |
LG325 | SNI | [54] | |
Zingiberene | SNI | [56] | |
SAHA | SNI/Trigeminal inflammatory compression/SNL/PSNL/CCI/Bone cancer | [28,45,47,57,66,70,71,76,79,86] | |
Carbamazepine | Trigeminal neuralgia | [67] | |
CAY10683 | SNL | [72] | |
Trichostatin A | PSNL/Bone cancer/CCI | [76,82,83,84,85] | |
Valproic acid | PSNL | [76,84] | |
JNJ26481585 (quinostat) | Chemotrerapy-induced neuropathy | [129] | |
Bromodomain and extraterminal (BET) | i-BET762 | SNI | [57] |
JQ1 | Spinal cord injury | [98] | |
Histone deacetylase-bromodomain-containing proteins (HDAC/BRD) | SUM52 | SNI | [58] |
SUM35 | SNI | [58] | |
Silent information regulator (SIRT) | Resveratrol (activator) | Bortezomib-induced neuropathy | [62] |
SRT1720 (activator) | Bortezomib-induced neuropathy/CCI | [62,64] | |
Histone acetyltransferase (HAT) | Anacardic acid | PSNL | [88,89] |
Histone methyltranserase G9a | UNC0638 | SNL | [45,113] |
BIX01294 | SNL | [112] | |
Enhancer of the histone methyltransferase zeste homolog-2 (EZH2) | GSK503 | SNL | [45] |
Lysine demethylase 7A (KDM7A) | NCDM-64 | Chemotherapy-induced neuropathy | [116] |
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Pethő, G.; Kántás, B.; Horváth, Á.; Pintér, E. The Epigenetics of Neuropathic Pain: A Systematic Update. Int. J. Mol. Sci. 2023, 24, 17143. https://doi.org/10.3390/ijms242417143
Pethő G, Kántás B, Horváth Á, Pintér E. The Epigenetics of Neuropathic Pain: A Systematic Update. International Journal of Molecular Sciences. 2023; 24(24):17143. https://doi.org/10.3390/ijms242417143
Chicago/Turabian StylePethő, Gábor, Boglárka Kántás, Ádám Horváth, and Erika Pintér. 2023. "The Epigenetics of Neuropathic Pain: A Systematic Update" International Journal of Molecular Sciences 24, no. 24: 17143. https://doi.org/10.3390/ijms242417143