Histone post-translational modifications as potential therapeutic targets for pain management

Epigenetic changes play a decisive role in the transition from acute to chronic tissue-injury-associated pain by supporting maladaptive molecular changes in neurons and glial cells.PTMs at histone tails are of particular importance. They modulate pain-induced gene transcription by regulating DNA–histone interactions and the binding of other proteins to the chromatin.A shift in HAT/HDAC interactions has been observed in the transition from immediate to lasting pain.Targeting EZH2, a histone methyltransferase enzyme, could serve as a potential novel analgesic treatment for neuropathic pain by preventing microglial activation and the expression of proinflammatory mediators.Transient phosphorylation of histone H3 has recently been identified at spinal neurons following noxious stimuli. Blockage of its effector kinases prevents the development of inflammatory heat hyperalgesia. Effective pharmacological management of pain associated with tissue pathology is an unmet medical need. Transcriptional modifications in nociceptive pathways are pivotal for the development and the maintenance of pain associated with tissue damage. Accumulating evidence has shown the importance of the epigenetic control of transcription in nociceptive pathways via histone post-translational modifications (PTMs). Hence, histone PTMs could be targets for novel effective analgesics. Here, we discuss the current understanding of histone PTMs in the modulation of gene expression affecting nociception and pain phenotypes following tissue injury. We also provide a critical view of the translational implications of preclinical models and discuss opportunities and challenges of targeting histone PTMs to relieve pain in clinically relevant tissue injuries. Effective pharmacological management of pain associated with tissue pathology is an unmet medical need. Transcriptional modifications in nociceptive pathways are pivotal for the development and the maintenance of pain associated with tissue damage. Accumulating evidence has shown the importance of the epigenetic control of transcription in nociceptive pathways via histone post-translational modifications (PTMs). Hence, histone PTMs could be targets for novel effective analgesics. Here, we discuss the current understanding of histone PTMs in the modulation of gene expression affecting nociception and pain phenotypes following tissue injury. We also provide a critical view of the translational implications of preclinical models and discuss opportunities and challenges of targeting histone PTMs to relieve pain in clinically relevant tissue injuries. Physical or chemical stressors that have the potential to damage tissue integrity induce the immediate development of a pain experience. This type of pain is essential for survival, develops through the activity of the naïve pain-signalling (nociceptive) pathways, and ceases within seconds if the tissues are removed from the stressor and no damage occurs. In the case of tissue damage, a qualitatively and quantitatively different pain experience develops that lasts until the tissue integrity is restored although it often persists beyond damage resolution. While the development of lasting pain on tissue damage constitutes a fundamental component of an adaptive response to restore homeostasis, when the pain experience persists beyond serving any biological function it becomes a pathological condition, a disease on its own, and is considered maladaptive [1.Raja S.N. et al.The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises.Pain. 2020; 161: 1976-1982Crossref PubMed Scopus (557) Google Scholar,2.Walters E.T. Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury.Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2019; 37420190277Crossref PubMed Scopus (11) Google Scholar]. Importantly, lasting pain has a devastating effect on quality of life. However, analgesics, which would reduce pain effectively and potently to an acceptable level, are lacking. Lasting pain arises following plastic changes in cellular signalling that lead to increased neural excitability and activity, known as sensitisation [3.Tsagareli M. Pain and memory: do they share similar mechanisms?.World J. Neurosci. 2013; 3: 39-48Crossref Google Scholar]. When no neuronal tissues are damaged, sensitisation is driven by the inflammatory reaction, which follows the tissue damage [4.Abdulkhaleq L.A. et al.The crucial roles of inflammatory mediators in inflammation: a review.Vet. World. 2018; 11: 627-635Crossref PubMed Scopus (218) Google Scholar]. If the damage involves peripheral sensory nerve fibres, injury-induced signals in primary sensory neurons are typically the driving force for sensitisation. Sensitisation in primary sensory neurons is termed peripheral sensitisation, while central sensitisation refers to increased excitability in the central nervous system [5.Colloca L. et al.Neuropathic pain.Nat. Rev. Dis. Primers. 2017; 3: 17002Crossref PubMed Scopus (835) Google Scholar]. Sensitisation occurs all along the nociceptive pathway. However, it has been best studied in nociceptive primary sensory neurons, which reside in dorsal root ganglia (DRG), and the spinal dorsal horn [2.Walters E.T. Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury.Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2019; 37420190277Crossref PubMed Scopus (11) Google Scholar,3.Tsagareli M. Pain and memory: do they share similar mechanisms?.World J. Neurosci. 2013; 3: 39-48Crossref Google Scholar,5.Colloca L. et al.Neuropathic pain.Nat. Rev. Dis. Primers. 2017; 3: 17002Crossref PubMed Scopus (835) Google Scholar]. Sensitisation is described by three mechanistically and temporarily distinct molecular changes that underpin the transformation of the initial noxious experience into a lasting pain associated with tissue injury [6.Yekkirala A.S. et al.Breaking barriers to novel analgesic drug development.Nat. Rev. Drug Discov. 2017; 16: 545-564Crossref PubMed Scopus (154) Google Scholar]. Immediate events occur instantly after sustained stimulation of primary sensory neurons or nociceptive input into the spinal dorsal horn and are due to self-amplification of currents carried by various ion channels [7.Yam M.F. et al.General pathways of pain sensation and the major neurotransmitters involved in pain regulation.Int. J. Mol. Sci. 2018; 19: 2164Crossref Scopus (145) Google Scholar]. The early signals occur within seconds to minutes after the start of a sustained noxious stimulus and are mediated by PTMs such as phosphorylation of various membrane and cytoplasmic molecules [8.Laedermann C.J. et al.Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.Front. Pharmacol. 2015; 6: 263Crossref PubMed Scopus (45) Google Scholar,9.Ji R.R. Peripheral and central mechanisms of inflammatory pain, with emphasis on MAP kinases.Curr. Drug. Targets Inflamm. Allergy. 2004; 3: 299-303Crossref PubMed Scopus (109) Google Scholar]. Finally, the third type of events that are fundamental for the long-term maintenance of the sensitised state is characterised by transcriptional changes that occur from hours to days after the injury in neuronal and glial cells [10.Woolf C.J. Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain.Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7723-7730Crossref PubMed Scopus (464) Google Scholar,11.Ji R.R. Woolf C.J. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain.Neurobiol. Dis. 2001; 8: 1-10Crossref PubMed Scopus (583) Google Scholar]. As a result, their phenotype is significantly altered for a prolonged period of time. Epigenetic mechanisms are fundamental in controlling transcription and, in the nervous system, they are strongly regulated by the activity of the cells [12.Sweatt J.D. 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In the nociceptive system, epigenetic regulation has been suggested to be pivotal in the development and maintenance of tissue-injury-associated pain through supporting long-lasting molecular changes [16.Topham L. et al.The transition from acute to chronic pain: dynamic epigenetic reprogramming of the mouse prefrontal cortex up to 1 year after nerve injury.Pain. 2020; 161: 2394-2409Crossref PubMed Scopus (8) Google Scholar]. Epigenetic modifications include inducible marks on chromatin (Box 1) such as DNA methylation or PTMs of histones. Histone PTMs, which are among the best-studied epigenetic mechanisms, are particularly interesting as, via the regulation of the myriad enzymes that add (writers), recognise (readers), or remove (erasers), these marks may provide specific control of gene expression. Although still in their infancy, the number of basic and clinical studies on the role of histone PTMs in pain has increased considerably in the past several years. Hence, there is an urgent need to critically review the available data to realistically evaluate the analgesic potential of controlling histone PTMs. This will help in finding the most appropriate avenues for further studies and ways to utilise the analgesic potential of controlling histone PTMs. Accordingly, subsequent sections of this review discuss histone PTMs (Figure 1) in the context of the development and maintenance of lasting pain experiences (outlined in Table 1) and critically evaluate preclinical and clinical data on the analgesic effects of controlling various writers, readers, or erasers (outlined in Figure 2 and Table 2). While this review focuses on PTMs in the nociceptive pathway, readers should note that epigenetic changes also occur in injured/inflamed non-neuronal tissues and are fundamental in maintaining the drive for peripheral sensitisation through the production of agents acting on primary sensory neurons. However, a discussion of epigenetic changes in injured/inflamed tissues is beyond the scope of this review.Box 1The structure of chromatinChromatin: a complex of DNA and proteins found in the nucleus of eukaryotic cells. DNA is compacted and wrapped around proteins to physically fit in the nucleus.Nucleosome: the smallest unit of chromatin; a globular unit comprising intranucleosome DNA wrapped around a histone octamer.Intranucleosome DNA: 145–147 bp of DNA running one and three-quarter turns around the histone octamer.Histone octamer: contains two copies of each of the core histones H2A, H2B, H3, and H4. These proteins assemble in pairs (H2A with H2B, H3 with H4) and merge to form the octamer.Beads-on-a-string structural model: each nucleosome is joined to adjacent nucleosomes by the linker DNA, a portion of 10–70 bp. In that conformation, the genes within can be transcriptionally active.Histone H1: an outer-nucleosome histone that stabilises the nucleosome. It can interact to further package the chromatin into a 30-nm fibre.Euchromatin: open chromatin. It is loosely packed and easily accessed by the transcriptional machinery.Heterochromatin: densely compacted chromatin, consequently closed to transcription. Heterochromatin is classified as two types: facultative heterochromatin, which differs by cell type; and constitutive heterochromatin, which is similar in all cell types and has a role in structural integrity (e.g., centromeres, telomers).Nucleosome sliding: nucleosomes can move translationally onto adjacent DNA sequences. The nucleosome remodels through time due to passive movements or by active processes involving remodelling proteins.Table 1List of changes in histone PTMs and associated proteins observed in nociceptive modelsPTM/enzymeAnimalModelSiteBehaviour assessedTarget (gene or enzyme)RefsH3K4me3, H3K9me2, H3K27me3RatSNLDRGMechanicalPanx1[21.Zhang Y. et al.Pannexin-1 up-regulation in the dorsal root ganglion contributes to neuropathic pain development.J. Biol. Chem. 2015; 290: 14647-14655Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]H3K27me3RatPartial SNLSC neurons, microgliaThermal, mechanicalEZH2[86.Li J. et al.EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia.Nat. Neurosci. 2013; 16: 1745-1753Crossref PubMed Scopus (103) Google Scholar]H3K9me2, H3K27me3, G9aRat, mouseSNLSC neurons, DRGThermal, mechanicalKcna4, Kcnd2, Kcnq2, Kcnma1[24.Laumet G. et al.G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain transition.Nat. Neurosci. 2015; 18: 1746-1755Crossref PubMed Scopus (110) Google Scholar]H3K9me2, G9aMouseSNL, CCIDRGThermal, mechanical, coldKcna2[26.Liang L. et al.G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons.Sci. Rep. 2016; 6: 37704Crossref PubMed Scopus (52) Google Scholar]G9a, C/EBPβMouseCCIDRGThermal, mechanical, coldOprm1, Kcna2[25.Li Z. et al.The transcription factor C/EBPβ in the dorsal root ganglion contributes to peripheral nerve trauma-induced nociceptive hypersensitivity.Sci. Signal. 2017; 10eaam5345PubMed Google Scholar]JMJD6RatCCISC neuronsThermal, mechanicalNF-κB p-p65[27.Wen C. et al.JMJD6 exerts function in neuropathic pain by regulating NF-κB following peripheral nerve injury in rats.Int. J. Mol. Med. 2018; 42: 633-642PubMed Google Scholar]H3ac, H4acRatSNL, CFA injectionDRG neurons and glial cellsMechanical–[31.Liang L. Tao Y.X. Expression of acetyl-histone H3 and acetyl-histone H4 in dorsal root ganglion and spinal dorsal horn in rat chronic pain models.Life Sci. 2018; 211: 182-188Crossref PubMed Scopus (7) Google Scholar]CFA injectionSC neuronsThermal, mechanicalKCC2[36.Lin C.R. et al.Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund’s adjuvant (CFA).Eur. J. Pain. 2017; 21: 309-321Crossref PubMed Scopus (21) Google Scholar]MouseSNLDRG neurons–bdnf[37.Uchida H. et al.Epigenetic regulation of BDNF expression in the primary sensory neurons after peripheral nerve injury: implications in the development of neuropathic pain.Neuroscience. 2013; 240: 147-154Crossref PubMed Scopus (56) Google Scholar]H3acRatCCISC neuronsThermal, mechanicalWnt3a[38.Feng W. et al.Epigenetic modulation of Wnt signaling contributes to neuropathic pain in rats.Mol. Med. Rep. 2015; 12: 4727-4733Crossref PubMed Scopus (16) Google Scholar]Rat, mouseCFA injection, SNLNRMThermalGad2, Gad65[33.Zhang Z. et al.Epigenetic suppression of GAD65 expression mediates persistent pain.Nat. Med. 2011; 17: 1448-1455Crossref PubMed Scopus (206) Google Scholar]H3K9aMouseTICTrigeminal gangliaMechanical34 various genes[32.Danaher R.J. et al.Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model.Mol. Pain. 2018; 141744806918796763Crossref Scopus (20) Google Scholar]RatSNLDRGMechanicalPanx1[21.Zhang Y. et al.Pannexin-1 up-regulation in the dorsal root ganglion contributes to neuropathic pain development.J. Biol. Chem. 2015; 290: 14647-14655Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]Elevated corticosteroids (CORTs)Central amygdala (CeA)Somatic and visceral hypersensitivity and anxiety-like behaviourscrf[34.Tran L. et al.Epigenetic modulation of chronic anxiety and pain by histone deacetylation.Mol. Psychiatry. 2015; 20: 1219-1231Crossref PubMed Scopus (78) Google Scholar]H3K27aMouseCFA, CCIDRGMechanicalGrm2[48.Notartomaso S. et al.Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain.Mol. Pain. 2017; 131744806917697009Crossref Scopus (19) Google Scholar]NRSF, H4acMouseSNLDRGThermal, mechanicalMOP, Nav1.8[35.Uchida H. et al.Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain.J. Neurosci. 2010; 30: 4806-4814Crossref PubMed Scopus (151) Google Scholar]p300-CBPRatCCISC neuronsThermal, mechanicalCOX2, BDNF[39.Zhu X.Y. et al.p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI).Mol. Pain. 2012; 8: 84Crossref PubMed Scopus (57) Google Scholar]MouseFormalin injectionDRG–mGluR-2[41.Chiechio S. et al.Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.Mol. Pharmacol. 2009; 75: 1014-1020Crossref PubMed Scopus (160) Google Scholar]HDAC4MouseCFA injectionDRGThermal, mechanicalCalca, TRPV1[46.Crow M. et al.HDAC4 is required for inflammation-associated thermal hypersensitivity.FASEB J. 2015; 29: 3370-3378Crossref PubMed Scopus (23) Google Scholar]H3S10pRatBurn injury, carrageenan, capsaicin injection, electrical stimulationSC neuronsThermalcFos[65.Torres-Pérez J.V. et al.Phosphorylated histone 3 at serine 10 identifies activated spinal neurons and contributes to the development of tissue injury-associated pain.Sci. Rep. 2017; 7: 41221Crossref PubMed Scopus (9) Google Scholar]Formalin, capsaicin injectionNocifensive behaviourZif268[66.Tochiki K.K. et al.The mitogen and stress-activated protein kinase 1 regulates the rapid epigenetic tagging of dorsal horn neurons and nocifensive behaviour.Pain. 2016; 157: 2594-2604Crossref PubMed Scopus (10) Google Scholar] Open table in a new tab Figure 2Changes in histone post-translational modifications (PTMs) associated with pain processing in preclinical models.Show full captionIn vivo pain models include scalding-type burn injury, orofacial or intraplantar injections (complete Freund’s adjuvant, formalin, carrageenan, or capsaicin), spinal nerve ligation (SNL), and chronic constriction injury (CCI). Once activated, nociceptors send signals to the spinal cord and, ultimately, the brain, where the noxious activation is perceived. Nociceptors reside in the dorsal root ganglion (DRG) (right column). The figure summarises histone PTMs associated with changes in gene expression observed during pain paradigms at the spinal cord (central column) and DRG (right column) level. Created with BioRender.com.https://www.cell.com/cms/asset/eaff29d8-2e30-41a6-897b-7541b0ff9c7f/mmc1.mp4Loading ... Download .mp4 (1.68 MB) Help with .mp4 files Figure360: An author presentation of Figure 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Summary of pharmacological targets and mechanisms of action for various epigenetic drugs targeting histone PTMs during pain paradigmsPreclinicalEpigenetic modifierChemical nameTarget/selectivityAnimal modelAdministrationPain modalityRefsHATIACAHATMice: PSLi.p.Hypersensitivity[87.Kiguchi N. et al.Epigenetic upregulation of CCL2 and CCL3 via histone modifications in infiltrating macrophages after peripheral nerve injury.Cytokine. 2013; 64: 666-672Crossref PubMed Scopus (58) Google Scholar]Mice: incision in hind paw skini.p.Mechanical and thermal hypersensitivity[88.Sun Y. et al.Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice.Anesthesiology. 2013; 119: 1198-1208Crossref PubMed Scopus (59) Google Scholar]C646HAT (p300/CBP)Rats: CCIi.t.Thermal and mechanical hypersensitivity[39.Zhu X.Y. et al.p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI).Mol. Pain. 2012; 8: 84Crossref PubMed Scopus (57) Google Scholar]Curcumin (diferuloylmethane)HAT (p300/CBP)Rats: CCIi.p.Hypersensitivity in neuropathy[40.Zhu X. et al.Curcumin alleviates neuropathic pain by inhibiting p300/CBP histone acetyltransferase activity-regulated expression of BDNF and cox-2 in a rat model.PLoS One. 2014; 9e91303Crossref PubMed Scopus (106) Google Scholar]Mice: OIHi.p.Thermal and mechanical hypersensitivity[43.Liang D.Y. et al.Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice.J. Pain. 2013; 14: 36-47Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar]HDACI4-PBHDAC class IIaMice: CFAi.t.Thermal hypersensitivity[44.Bai G. et al.Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.Mol. Pain. 2010; 6: 51Crossref PubMed Scopus (126) Google Scholar]BaicalinHDAC1Rats: SNLi.t.Thermal and mechanical hypersensitivity[89.Cherng C.H. et al.Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats.J. Formos. Med. Assoc. 2014; 113: 513-520Crossref PubMed Scopus (82) Google Scholar]LAQ824HDAC class IIMice: CFAi.t.Thermal hypersensitivity[44.Bai G. et al.Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.Mol. Pain. 2010; 6: 51Crossref PubMed Scopus (126) Google Scholar]MS-275HDAC (1 and 3 selectively)Mice: formalins.c.Persistent inflammatory pain second phase[41.Chiechio S. et al.Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.Mol. Pharmacol. 2009; 75: 1014-1020Crossref PubMed Scopus (160) Google Scholar]MS-275 and MGCD0103HDAC class IRats: SNL, PSL, and peripheral neuropathic pain induced by d4Ti.t.Thermal and mechanical hypersensitivity[51.Denk F. et al.HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain.Pain. 2013; 154: 1668-1679Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar]SAHAHDACs class I and IIRats and mice: CFA, SNLi.p. infusion into NRMChronic pain, thermal hypersensitivity[33.Zhang Z. et al.Epigenetic suppression of GAD65 expression mediates persistent pain.Nat. Med. 2011; 17: 1448-1455Crossref PubMed Scopus (206) Google Scholar]Mice: PSLLocal application i.pl.Hypersensitivity of C-fibres and injury-induced thermal and mechanical hypersensitivity[35.Uchida H. et al.Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain.J. Neurosci. 2010; 30: 4806-4814Crossref PubMed Scopus (151) Google Scholar]Mice: incision in hind pawi.p.Mechanical hypersensitivity exacerbated, no impact on thermal hypersensitivity[88.Sun Y. et al.Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice.Anesthesiology. 2013; 119: 1198-1208Crossref PubMed Scopus (59) Google Scholar]Mice: formalins.c.Persistent inflammatory pain second phase[41.Chiechio S. et al.Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.Mol. Pharmacol. 2009; 75: 1014-1020Crossref PubMed Scopus (160) Google Scholar]Mice: CFAi.t.Thermal hypersensitivity[44.Bai G. et al.Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.Mol. Pain. 2010; 6: 51Crossref PubMed Scopus (126) Google Scholar]Mice: OIHi.p.Thermal and mechanical hypersensitivity[43.Liang D.Y. et al.Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice.J. Pain. 2013; 14: 36-47Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar]Resveratrol (Sirt1 activator)HDAC class IIIRat: CCIi.t.Thermal and mechanical hypersensitivity[90.Yin Q. et al.Resveratrol facilitates pain attenuation in a rat model of neuropathic pain through the activation of spinal Sirt1.Reg. Anesth. Pain Med. 2013; 38: 93-99Crossref PubMed Scopus (61) Google Scholar]Sodium butyrateHDAC class I and IIRats: CCIOrallyNeuropathic pain hypersensitivity (including cold, mechanical, and thermal hypersensitivity)[50.Kukkar A. et al.Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats.J. Formos. Med. Assoc. 2014; 113: 921-928Crossref PubMed Scopus (49) Google Scholar]TSAHDAC class I and IIMice: CFAi.p.CFA-induced changes in WT mice but no hypersensitivity developed in GAD2−/- mice[33.Zhang Z. et al.Epigenetic suppression of GAD65 expression mediates persistent pain.Nat. Med. 2011; 17: 1448-1455Crossref PubMed Scopus (206) Google Scholar]Mice: CFAi.t.Thermal hypersensitivity[44.Bai G. et al.Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.Mol. Pain. 2010; 6: 51Crossref PubMed Scopus (126) Google Scholar]Mice: PSLLocal application i.pl.Hypersensitivity of C-fibres and injury-induced thermal and mechanical hypersensitivity[35.Uchida H. et al.Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain.J. Neurosci. 2010; 30: 4806-4814Crossref PubMed Scopus (151) Google Scholar,91.Matsushita Y. et al.HDAC inhibitors restore C-fibre sensitivity in experimental neuropathic pain model.Br. J. Pharmacol. 2013; 170: 991-998Crossref PubMed Scopus (53) Google Scholar]Female adult rats: endometriosiss.c.Thermal hypersensitivity[92.Lu Y. et al.Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice.Hum. Reprod. 2010; 25: 1014-1025Crossref PubMed Scopus (83) Google Scholar]Rats: repeated water-avoidance stressi.c.v. cannulaStress-induced visceral hypersensitivity[93.Tran L. et al.Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress.Psychoneuroendocrinology. 2013; 38: 898-906Crossref PubMed Scopus (94) Google Scholar]VPAHDAC class I (1–3 and 8) and class IIa (4, 5, 7, and 9)Rats: SNLOrallyNeuropathic pain hypersensitivity[94.Hobo S. et al.Up-regulation of spinal glutamate transporters contributes to anti-hypersensitive effects of valproate in rats after peripheral nerve injury.Neurosci. Lett. 2011; 502: 52-55Crossref PubMed Scopus (35) Google Scholar]Mice: PSLLocal application i.pl.Hypersensitivity of C-fibres and injury-induced thermal and mechanical hypersensitivity[35.Uchida H. et al.Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain.J. Neurosci. 2010; 30: 4806-4814Crossref PubMed Scopus (151) Google Scholar,91.Matsushita Y. et al.HDAC inhibitors restore C-fibre sensitivity in experimental neuropathic pain model.Br. J. Pharmacol. 2013; 170: 991-998Crossref PubMed Scopus (53) Google Scholar]Female adult rats: endometriosisOrallyThermal hypersensitivity[95.Liu M. et al.Valproic acid and progestin inhibit lesion growth and reduce hyperalgesia in experimentally induced endometriosis in rats.Reprod. Sci. 2012; 19: 360-373Crossref PubMed Scopus (46) Google Scholar]Mice: CFAi.t.Thermal hypersensitivity[44.Bai G. et al.Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.Mol. Pain. 2010; 6: 51Crossref PubMed Scopus (126) Google Scholar]Rat: SNLOrallyThermal hypersensitivity[96.Yoshizumi M. et al.Valproate prevents dysregulation of spinal glutamate and reduces the development of hypersensitivity in rats after peripheral nerve injury.J. Pain. 2013; 14: 1485-1491Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]Rat: forced swimi.p.Stress-induced somatic hyperalgesia and visceral hypersensitivity[97.Xu G.Z. et al.Valproate reverses stress-induced somatic hyperalgesia and visceral hypersensitivity by up-regulating spinal 5-HT2C receptor expression in female rats.Neuropharmacology. 2020; 165107926Crossref PubMed Scopus (10) Google Scholar]HPISB727651AMSK1 inhibitorMice: i.pl. formalin, i.pl. capsaicini.t.Thermal and mechanical hypersensitivity[66.Tochiki K.K. et al.The mitogen and stress-activated protein kinase 1 regulates the rapid epigenetic tagging of dorsal horn neurons and nocifensive behaviour.Pain. 2016; 157: 2594-2604Crossref PubMed Scopus (10) Google Scholar]Rats: i.pl. capsaicin, sustained electrical activationIncubating SC slices in the drug solutionThermal and mechanical hypersensitivity[65.Torres-Pérez J.V. et al.Phosphorylated histone 3 at serine 10 identifies activated spinal neurons and contributes to the development of tissue injury-associated pain.Sci. Rep. 2017; 7: 41221Crossref PubMed Scopus (9) Google Scholar]Clinically tested/approvedEpigenetic modifierChemical nameTargetClinical statusAdministrationPain modalityRefsHDACIGivinostat (ITF 2357)HDAC class I and IIPhase IIOrallyIdiopathic form of juvenile arthritis[98.Vojinovic J. et al.Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis.Arthritis Rheum. 2011; 63: 1452-1458Crossref PubMed Scopus (167) Google Scholar]RicolinostatSelective HDAC6Phase IIOrallyDiabetic neuropathic pain[54.Regenacy Pharmaceuticals L.L.C. Ricolinostat in patients with diabetic neuropathic pain.https://clinicaltrials.gov/ct2/show/NCT03176472Date: 2017Google Scholar]RomidepsinSelective HDAC6Approved for use in clinic against CTCL and PTCL; Phase II for multiple myelomai.v. infusionN/ASome multiple myeloma patients reported alleviated bone pain[99.Niesvizky R. et al.Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple