Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drugging the pain epigenome

Key Points

  • Pathophysiological pain such as inflammatory, neuropathic and cancer pain is characterized by increased pain sensitivity

  • Despite a number of approved analgesics, pain therapy is often unsatisfactory because of low efficacy and adverse effects

  • Pathophysiological pain is associated with a number of different types of epigenetic modulation

  • Future therapeutic interventions in patients who experience pain might target tissue-specific and cell-specific epigenetic mechanisms with histone deacetylase inhibitors, DNA methyltransferase inhibitors, and microRNA mimics or inhibitors

Abstract

More than 20% of adults worldwide experience different types of chronic pain, which are frequently associated with several comorbidities and a decrease in quality of life. Several approved painkillers are available, but current analgesics are often hampered by insufficient efficacy and/or severe adverse effects. Consequently, novel strategies for safe, highly efficacious treatments are highly desirable, particularly for chronic pain. Epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs (miRNAs) strongly affect the regulation of gene expression, potentially for long periods over years or even generations, and have been associated with pathophysiological pain. Several studies, mostly in animals, revealed that inhibitors of DNA methylation, activators and inhibitors of histone modification and modulators of miRNAs reverse a number of pathological changes in the pain epigenome, which are associated with altered expression of pain-relevant genes. This epigenetic modulation might then reduce the nociceptive response and provide novel therapeutic options for analgesic therapy of chronic pain states. However, a number of challenges, such as nonspecific effects and poor delivery to target cells and tissues, hinder the rapid development of such analgesics. In this Review, we critically summarize data on epigenetics and pain, focusing on challenges in clinical development as well as possible new approaches to the drug modulation of the pain epigenome.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Epigenetic mechanisms.
Figure 2: miRNA processing.

Similar content being viewed by others

References

  1. Gershell, L. & Goater, J. J. Making gains in pain. Nat. Rev. Drug Discov. 5, 889–890 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Melnikova, I. Pain market. Nat. Rev. Drug Discov. 9, 589–590 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Bird, A. Perceptions of epigenetics. Nature 447, 396–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Rudenko, A. & Tsai, L. H. Epigenetic modifications in the nervous system and their impact upon cognitive impairments. Neuropharmacology 80, 70–82 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Guan, J. S., Xie, H. & Ding, X. The role of epigenetic regulation in learning and memory. Exp. Neurol. 268, 30–36 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Halder, R. et al. DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat. Neurosci. 19, 102–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Day, J. J. & Sweatt, J. D. DNA methylation and memory formation. Nat. Neurosci. 13, 1319–1323 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ji, R. R., Kohno, T., Moore, K. A. & Woolf, C. J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 26, 696–705 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Kuner, R. Central mechanisms of pathological pain. Nat. Med. 16, 1258–1266 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Deans, C. & Maggert, K. A. What do you mean, “epigenetic”? Genetics 199, 887–896 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bai, G., Ren, K. & Dubner, R. Epigenetic regulation of persistent pain. Transl. Res. 165, 177–199 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Descalzi, G. et al. Epigenetic mechanisms of chronic pain. Trends Neurosci. 38, 237–246 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liang, L., Lutz, B. M., Bekker, A. & Tao, Y. X. Epigenetic regulation of chronic pain. Epigenomics 7, 235–245 (2015).

    CAS  PubMed  Google Scholar 

  14. Burridge, S. Target watch: drugging the epigenome. Nat. Rev. Drug Discov. 12, 92–93 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Ligon, C. O., Moloney, R. D. & Greenwood-Van Meerveld, B. Targeting epigenetic mechanisms for chronic pain: a valid approach for the development of novel therapeutics. J. Pharmacol. Exp. Ther. 357, 84–93 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Chen, T. & Dent, S. Y. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat. Rev. Genet. 15, 93–106 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Voss, T. C. & Hager, G. L. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat. Rev. Genet. 15, 69–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Rothbart, S. B. & Strahl, B. D. Interpreting the language of histone and DNA modifications. Biochim. Biophys. Acta 1839, 627–643 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Petty, E. & Pillus, L. Balancing chromatin remodeling and histone modifications in transcription. Trends Genet. 29, 621–629 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Keller, C. & Buhler, M. Chromatin-associated ncRNA activities. Chromosome Res. 21, 627–641 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Friedman, R. C., Farh, K. K., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Li, E. & Zhang, Y. DNA methylation in mammals. Cold Spring Harb. Perspect. Biol. 6, a019133 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Zentner, G. E. & Henikoff, S. Regulation of nucleosome dynamics by histone modifications. Nat. Struct. Mol. Biol. 20, 259–266 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shakespear, M. R., Halili, M. A., Irvine, K. M., Fairlie, D. P. & Sweet, M. J. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 32, 335–343 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Marmorstein, R. Structure and function of histone acetyltransferases. Cell. Mol. Life Sci. 58, 693–703 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K. & Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384–400 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Xu, W. S., Parmigiani, R. B. & Marks, P. A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541–5552 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Mann, B. S., Johnson, J. R., Cohen, M. H., Justice, R. & Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12, 1247–1252 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Jain, S. & Zain, J. Romidepsin in the treatment of cutaneous T-cell lymphoma. J. Blood Med. 2, 37–47 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, H. Z. et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin. Cancer Res. 21, 2666–2670 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Nervi, C., De Marinis, E. & Codacci-Pisanelli, G. Epigenetic treatment of solid tumours: a review of clinical trials. Clin. Epigenetics 7, 127 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Guha, M. HDAC inhibitors still need a home run, despite recent approval. Nat. Rev. Drug Discov. 14, 225–226 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Crow, M., Denk, F. & McMahon, S. B. Genes and epigenetic processes as prospective pain targets. Genome Med. 5, 12 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Falkenberg, K. J. & Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673–691 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Foulks, J. M. et al. Epigenetic drug discovery: targeting DNA methyltransferases. J. Biomol. Screen. 17, 2–17 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Franchini, D. M., Schmitz, K. M. & Petersen-Mahrt, S. K. 5-Methylcytosine DNA demethylation: more than losing a methyl group. Annu. Rev. Genet. 46, 419–441 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Wu, H. & Zhang, Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156, 45–68 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sharma, S., Kelly, T. K. & Jones, P. A. Epigenetics in cancer. Carcinogenesis 31, 27–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Grayson, D. R. et al. Reelin promoter hypermethylation in schizophrenia. Proc. Natl Acad. Sci. USA 102, 9341–9346 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nielsen, D. A. et al. Increased OPRM1 DNA methylation in lymphocytes of methadone-maintained former heroin addicts. Neuropsychopharmacology 34, 867–873 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Kaminskas, E. et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin. Cancer Res. 11, 3604–3608 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Kaminskas, E., Farrell, A. T., Wang, Y. C., Sridhara, R. & Pazdur, R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 10, 176–182 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Gore, S. D., Jones, C. & Kirkpatrick, P. Decitabine. Nat. Rev. Drug Discov. 5, 891–892 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Preall, J. B. & Sontheimer, E. J. RNAi: RISC gets loaded. Cell 123, 543–545 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Esquela-Kerscher, A. & Slack, F. J. Oncomirs — microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Sullivan, C. S. & Ganem, D. MicroRNAs and viral infection. Mol. Cell 20, 3–7 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Kartha, R. V. & Subramanian, S. MicroRNAs in cardiovascular diseases: biology and potential clinical applications. J. Cardiovasc. Transl. Res. 3, 256–270 (2010).

    Article  PubMed  Google Scholar 

  54. Zhao, J. et al. Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds. J. Neurosci. 30, 10860–10871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kynast, K. L., Russe, O. Q., Geisslinger, G. & Niederberger, E. Novel findings in pain processing pathways: implications for miRNAs as future therapeutic targets. Expert Rev. Neurother. 13, 515–525 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Niederberger, E., Kynast, K., Lotsch, J. & Geisslinger, G. MicroRNAs as new players in the pain game. Pain 152, 1455–1458 (2011).

    Article  PubMed  Google Scholar 

  57. Denk, F., McMahon, S. B. & Tracey, I. Pain vulnerability: a neurobiological perspective. Nat.Neurosci. 17, 192–200 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Connor, C. M. et al. Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome. Schizophr. Res. 140, 175–184 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Chomiak, T., Turner, N. & Hu, B. What we have learned about autism spectrum disorder from valproic acid. Patholog. Res. Int. 2013, 712758 (2013).

    PubMed  PubMed Central  Google Scholar 

  60. Jaffe, A. E. et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat. Neurosci. 19, 40–47 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. Hannon, E. et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat. Neurosci. 19, 48–54 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Schwarz, J. M., Hutchinson, M. R. & Bilbo, S. D. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J. Neurosci. 31, 17835–17847 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sweatt, J. D. The emerging field of neuroepigenetics. Neuron 80, 624–632 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Bell, J. T. et al. Differential methylation of the TRPA1 promoter in pain sensitivity. Nat. Commun. 5, 2978 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Gombert, S. et al. Epigenetic divergence in the TRPA1 promoter correlates with pressure pain thresholds in healthy individuals. Pain 158, 698–704 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Doehring, A., Geisslinger, G. & Lotsch, J. Epigenetics in pain and analgesia: an imminent research field. Eur. J. Pain 15, 11–16 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Niederberger, E. Epigenetics and pain [German]. Anaesthesist 63, 63–69 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Denk, F., Crow, M., Didangelos, A., Lopes, D. M. & McMahon, S. B. Persistent alterations in microglial enhancers in a model of chronic pain. Cell Rep. 15, 1771–1781 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Alvarado, S. et al. An epigenetic hypothesis for the genomic memory of pain. Front. Cell. Neurosci. 9, 88 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Buchheit, T., Van de Ven, T. & Shaw, A. Epigenetics and the transition from acute to chronic pain. Pain Med. 13, 1474–1490 (2012).

    Article  PubMed  Google Scholar 

  71. Lotsch, J. et al. Common non-epigenetic drugs as epigenetic modulators. Trends Mol. Med. 19, 742–753 (2013).

    Article  PubMed  CAS  Google Scholar 

  72. Yiannakopoulou, E. Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents — implications for cancer treatment and chemoprevention. Cell. Oncol. (Dordr.) 37, 167–178 (2014).

    Article  CAS  Google Scholar 

  73. Wilson, L. E. et al. Non-steroidal anti-inflammatory drug use and genomic DNA methylation in blood. PLoS ONE 10, e0138920 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Chang, P. Y. et al. Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction. Cardiovasc. Res. 99, 137–145 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Pereira, M. A. et al. Modulation by celecoxib and difluoromethylornithine of the methylation of DNA and the estrogen receptor-α gene in rat colon tumors. Carcinogenesis 25, 1917–1923 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Shen, R. et al. Reversibility of aberrant global DNA and estrogen receptor-α gene methylation distinguishes colorectal precancer from cancer. Int. J. Clin. Exp. Pathol. 2, 21–33 (2009).

    PubMed  Google Scholar 

  77. Cui, W., Hu, S. X., Tang, Z. Y. & Hu, K. Q. In-vivo effects and mechanisms of celecoxib-reduced growth of cyclooxygenase-2 (COX-2)-expressing versus COX-2-deleted human HCC xenografts in nude mice. Anticancer Drugs 19, 891–897 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, W. C. et al. microRNA expression pattern and its alteration following celecoxib intervention in human colorectal cancer. Exp. Ther. Med. 3, 1039–1048 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Saito, Y. et al. The tumor suppressor microRNA-29c is downregulated and restored by celecoxib in human gastric cancer cells. Int. J. Cancer 132, 1751–1760 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Wong, T. Y. et al. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice. BMC Cancer 14, 426 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Sun, H. et al. Morphine epigenomically regulates behavior through alterations in histone H3 lysine 9 dimethylation in the nucleus accumbens. J. Neurosci. 32, 17454–17464 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Doehring, A., Oertel, B. G., Sittl, R. & Lotsch, J. Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain. Pain 154, 15–23 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Knothe, C., Doehring, A., Ultsch, A. & Lotsch, J. Methadone induces hypermethylation of human DNA. Epigenomics 8, 167–179 (2016).

    Article  CAS  PubMed  Google Scholar 

  84. Hwang, C. K., Wagley, Y., Law, P. Y., Wei, L. N. & Loh, H. H. MicroRNAs in opioid pharmacology. J. Neuroimmune Pharmacol. 7, 808–819 (2012).

    Article  PubMed  Google Scholar 

  85. He, Y., Yang, C., Kirkmire, C. M. & Wang, Z. J. Regulation of opioid tolerance by let-7 family microRNA targeting the μ opioid receptor. J. Neurosci. 30, 10251–10258 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Verdu, B., Decosterd, I., Buclin, T., Stiefel, F. & Berney, A. Antidepressants for the treatment of chronic pain. Drugs 68, 2611–2632 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Dharmshaktu, P., Tayal, V. & Kalra, B. S. Efficacy of antidepressants as analgesics: a review. J. Clin. Pharmacol. 52, 6–17 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Moore, R. A., Wiffen, P. J., Derry, S., Toelle, T. & Rice, A. S. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 4, CD007938 (2014).

    Google Scholar 

  89. Wiffen, P. J., Derry, S., Moore, R. A. & Kalso, E. A. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 4, CD005451 (2014).

    Google Scholar 

  90. Sisignano, M., Baron, R., Scholich, K. & Geisslinger, G. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat. Rev. Neurol. 10, 694–707 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, Y. et al. Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury. J. Neurotrauma 28, 259–268 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Schmidt, U. et al. Therapeutic action of fluoxetine is associated with a reduction in prefrontal cortical miR-1971 expression levels in a mouse model of posttraumatic stress disorder. Front. Psychiatry 4, 66 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Perisic, T. et al. Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes. Neuropsychopharmacology 35, 792–805 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Mao, X. et al. The tricyclic antidepressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases: in vitro and in silico evidence. Mol. Pharmacol. 79, 672–680 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Imai, S. et al. Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. Brain 136, 828–843 (2013).

    Article  PubMed  Google Scholar 

  96. Zhang, Y., Laumet, G., Chen, S. R., Hittelman, W. N. & Pan, H. L. Pannexin-1 up-regulation in the dorsal root ganglion contributes to neuropathic pain development. J. Biol. Chem. 290, 14647–14655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kiguchi, N., Kobayashi, Y., Saika, F. & Kishioka, S. Epigenetic upregulation of CCL2 and CCL3 via histone modifications in infiltrating macrophages after peripheral nerve injury. Cytokine 64, 666–672 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Kiguchi, N., Saika, F., Kobayashi, Y. & Kishioka, S. Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation. Biomol. Concepts 5, 265–273 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Laumet, G. et al. G9a is essential for epigenetic silencing of K channel genes in acute-to-chronic pain transition. Nat. Neurosci. 18, 1746–1755 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Liang, L. et al. G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Sci. Rep. 6, 37704 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yang, X. J. & Seto, E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26, 5310–5318 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Dekker, F. J., van den Bosch, T. & Martin, N. I. Small molecule inhibitors of histone acetyltransferases and deacetylases are potential drugs for inflammatory diseases. Drug Discov. Today 19, 654–660 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Crow, M. et al. HDAC4 is required for inflammation-associated thermal hypersensitivity. FASEB J. 29, 3370–3378 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bai, G., Wei, D., Zou, S., Ren, K. & Dubner, R. Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia. Mol. Pain 6, 51 (2010).

    PubMed  PubMed Central  Google Scholar 

  105. Chiechio, S. et al. Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain. Mol. Pharmacol. 75, 1014–1020 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Tran, L., Chaloner, A., Sawalha, A. H. & Greenwood Van-Meerveld, B. Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress. Psychoneuroendocrinology 38, 898–906 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Denk, F. et al. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain 154, 1668–1679 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhang, Z., Cai, Y. Q., Zou, F., Bie, B. & Pan, Z. Z. Epigenetic suppression of GAD65 expression mediates persistent pain. Nat. Med. 17, 1448–1455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shen, X. et al. Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain. Pharmacol. Rep. 66, 49–55 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Moloney, R. D., Stilling, R. M., Dinan, T. G. & Cryan, J. F. Early-life stress-induced visceral hypersensitivity and anxiety behavior is reversed by histone deacetylase inhibition. Neurogastroenterol. Motil. 27, 1831–1836 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. 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 8, 84 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Capasso, K. E. et al. Effect of histone deacetylase inhibitor JNJ-26481585 in pain. J. Mol. Neurosci. 55, 570–578 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Zammataro, M., Sortino, M. A., Parenti, C., Gereau, R. W. IV & Chiechio, S. HDAC and HAT inhibitors differently affect analgesia mediated by group II metabotropic glutamate receptors. Mol. Pain 10, 68 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Cao, D. Y., Bai, G., Ji, Y. & Traub, R. J. Epigenetic upregulation of metabotropic glutamate receptor 2 in the spinal cord attenuates oestrogen-induced visceral hypersensitivity. Gut 64, 1913–1920 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Liang, D. Y., Li, X. & Clark, J. D. Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice. J. Pain 14, 36–47 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Vojinovic, J. et al. Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 63, 1452–1458 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Niesvizky, R. et al. Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer 117, 336–342 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Mottamal, M., Zheng, S., Huang, T. L. & Wang, G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20, 3898–3941 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Strevel, E. L., Ing, D. J. & Siu, L. L. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J. Clin. Oncol. 25, 3362–3371 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Backs, J. & Olson, E. N. Control of cardiac growth by histone acetylation/deacetylation. Circ. Res. 98, 15–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Downes, M., Ordentlich, P., Kao, H. Y., Alvarez, J. G. & Evans, R. M. Identification of a nuclear domain with deacetylase activity. Proc. Natl Acad. Sci. USA 97, 10330–10335 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Halili, M. A., Andrews, M. R., Sweet, M. J. & Fairlie, D. P. Histone deacetylase inhibitors in inflammatory disease. Curr. Top. Med. Chem. 9, 309–319 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Brogdon, J. L. et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109, 1123–1130 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Choi, J. H. et al. Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 25, 2404–2409 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Qi, F. et al. Promoter demethylation of cystathionine-β-synthetase gene contributes to inflammatory pain in rats. Pain 154, 34–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Tajerian, M. et al. Peripheral nerve injury is associated with chronic, reversible changes in global DNA methylation in the mouse prefrontal cortex. PLoS ONE 8, e55259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wang, Y. et al. Intrathecal 5-azacytidine inhibits global DNA methylation and methyl- CpG-binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury. Brain Res. 1418, 64–69 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Brekken, R. A. & Sage, E. H. SPARC, a matricellular protein: at the crossroads of cell–matrix communication. Matrix Biol. 19, 816–827 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Gruber, H. E. et al. Targeted deletion of the SPARC gene accelerates disc degeneration in the aging mouse. J. Histochem. Cytochem. 53, 1131–1138 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Tajerian, M. et al. DNA methylation of SPARC and chronic low back pain. Mol. Pain 7, 65 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhou, X. L. et al. Increased methylation of the MOR gene proximal promoter in primary sensory neurons plays a crucial role in the decreased analgesic effect of opioids in neuropathic pain. Mol. Pain 10, 51 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Viet, C. T. et al. Decitabine rescues cisplatin resistance in head and neck squamous cell carcinoma. PLoS ONE 9, e112880 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Viet, C. T. et al. Demethylating drugs as novel analgesics for cancer pain. Clin. Cancer Res. 20, 4882–4893 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ritchie, E. K. Safety and efficacy of azacitidine in the treatment of elderly patients with myelodysplastic syndrome. Clin. Interv. Aging 7, 165–173 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lee, Y. G. et al. Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br. J. Haematol. 161, 339–347 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Stresemann, C., Brueckner, B., Musch, T., Stopper, H. & Lyko, F. Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res. 66, 2794–2800 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Stresemann, C. & Lyko, F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer 123, 8–13 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Metzeler, K. H. et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 26, 1106–1107 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Leinders, M. et al. Increased cutaneous miR-let-7d expression correlates with small nerve fiber pathology in patients with fibromyalgia syndrome. Pain 157, 2493–2503 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Zhou, Q. et al. Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1. Gut 65, 797–805 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Pan, Z. et al. Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIγ. J. Neurosci. 34, 9476–9483 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Kynast, K. L., Russe, O. Q., Moser, C. V., Geisslinger, G. & Niederberger, E. Modulation of central nervous system-specific microRNA-124a alters the inflammatory response in the formalin test in mice. Pain 154, 368–376 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Willemen, H. L. et al. MicroRNA-124 as a novel treatment for persistent hyperalgesia. J. Neuroinflamm. 9, 143 (2012).

    Article  CAS  Google Scholar 

  144. Favereaux, A. et al. Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. EMBO J. 30, 3830–3841 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chattopadhyay, M., Zhou, Z., Hao, S., Mata, M. & Fink, D. J. Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. Mol. Pain 8, 17 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Imai, S. et al. Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain. J. Neurosci. 31, 15294–15299 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Bali, K. K. et al. Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain. EMBO Mol. Med. 5, 1740–1758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Tsuda, N., Mine, T., Ioannides, C. G. & Chang, D. Z. Synthetic microRNA targeting glioma-associated antigen-1 protein. Methods Mol. Biol. 487, 435–449 (2009).

    CAS  PubMed  Google Scholar 

  149. Krutzfeldt, J. et al. Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res. 35, 2885–2892 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ebert, M. S. & Sharp, P. A. MicroRNA sponges: progress and possibilities. RNA 16, 2043–2050 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Haraguchi, T., Ozaki, Y. & Iba, H. Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 37, e43 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Doleshal, M. et al. Evaluation and validation of total RNA extraction methods for microRNA expression analyses in formalin-fixed, paraffin-embedded tissues. J. Mol. Diagn. 10, 203–211 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Krutzfeldt, J., Poy, M. N. & Stoffel, M. Strategies to determine the biological function of microRNAs. Nat. Genet. 38 (Suppl.), S14–S19 (2006).

    Article  PubMed  CAS  Google Scholar 

  154. Trang, P. et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol. Ther. 19, 1116–1122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Bridge, A. J., Pebernard, S., Ducraux, A., Nicoulaz, A. L. & Iggo, R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat. Genet. 34, 263–264 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Jones, P. A., Issa, J. P. & Baylin, S. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630–641 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. el Bahhaj, F., Dekker, F. J., Martinet, N. & Bertrand, P. Delivery of epidrugs. Drug Discov. Today 19, 1337–1352 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Feinberg, A. P., Koldobskiy, M. A. & Gondor, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284–299 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Diesch, J. et al. A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin. Epigenetics 8, 71 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Burggren, W. W. Dynamics of epigenetic phenomena: intergenerational and intragenerational phenotype 'washout'. J. Exp. Biol. 218, 80–87 (2015).

    Article  PubMed  Google Scholar 

  161. Sisignano, M., Parnham, M. J. & Geisslinger, G. Drug repurposing for the development of novel analgesics. Trends Pharmacol. Sci. 37, 172–183 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. Chuang, D. M., Leng, Y., Marinova, Z., Kim, H. J. & Chiu, C. T. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci. 32, 591–601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. D'Mello, S. R. Histone deacetylases as targets for the treatment of human neurodegenerative diseases. Drug News Perspect. 22, 513–524 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kungulovski, G. & Jeltsch, A. Epigenome editing: state of the art, concepts, and perspectives. Trends Genet. 32, 101–113 (2016).

    Article  CAS  PubMed  Google Scholar 

  165. Stricker, S. H., Koferle, A. & Beck, S. From profiles to function in epigenomics. Nat. Rev. Genet. 18, 51–66 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Phillips, D. M. The presence of acetyl groups of histones. Biochem. J. 87, 258–263 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Filippakopoulos, P. & Knapp, S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 13, 337–356 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Dong, K. B. et al. DNA methylation in ES cells requires the lysine methyltransferase G9a but not its catalytic activity. EMBO J. 27, 2691–2701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Guo, X. et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517, 640–644 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. Zhang, T., Cooper, S. & Brockdorff, N. The interplay of histone modifications — writers that read. EMBO Rep. 16, 1467–1481 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Huston, A., Arrowsmith, C. H., Knapp, S. & Schapira, M. Probing the epigenome. Nat. Chem. Biol. 11, 542–545 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

    Article  CAS  PubMed  Google Scholar 

  174. Illingworth, R. S. & Bird, A. P. CpG islands — 'a rough guide'. FEBS Lett. 583, 1713–1720 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. Honda, T. et al. Demethylation of MAGE promoters during gastric cancer progression. Br. J. Cancer 90, 838–843 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ziller, M. J. et al. Charting a dynamic DNA methylation landscape of the human genome. Nature 500, 477–481 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yagi, S. et al. DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression. Genome Res. 18, 1969–1978 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654–1663 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. Tran, L., Schulkin, J., Ligon, C. O. & Greenwood-Van Meerveld, B. Epigenetic modulation of chronic anxiety and pain by histone deacetylation. Mol. Psychiatry 20, 1219–1231 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Kiguchi, N. et al. Epigenetic augmentation of the macrophage inflammatory protein 2/C-X-C chemokine receptor type 2 axis through histone H3 acetylation in injured peripheral nerves elicits neuropathic pain. J. Pharmacol. Exp. Ther. 340, 577–587 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Stein, C., Millan, M. J. & Herz, A. Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds. Pharmacol. Biochem. Behav. 31, 445–451 (1988).

    Article  CAS  PubMed  Google Scholar 

  182. Clark, A. K., Gentry, C., Bradbury, E. J., McMahon, S. B. & Malcangio, M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur. J. Pain 11, 223–230 (2007).

    Article  PubMed  Google Scholar 

  183. Dubuisson, D. & Dennis, S. G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174 (1977).

    Article  CAS  PubMed  Google Scholar 

  184. Bradesi, S. et al. Repeated exposure to water avoidance stress in rats: a new model for sustained visceral hyperalgesia. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G42–G53 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Walder, R. Y., Gautam, M., Wilson, S. P., Benson, C. J. & Sluka, K. A. Selective targeting of ASIC3 using artificial miRNAs inhibits primary and secondary hyperalgesia after muscle inflammation. Pain 152, 2348–2356 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kim, S. H. & Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–363 (1992).

    Article  CAS  Google Scholar 

  187. Choi, Y., Yoon, Y. W., Na, H. S., Kim, S. H. & Chung, J. M. Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain 59, 369–376 (1994).

    Article  CAS  Google Scholar 

  188. Lin, T. B. et al. Modulation of nerve injury-induced HDAC4 cytoplasmic retention contributes to neuropathic pain in rats. Anesthesiology 123, 199–212 (2015).

    Article  CAS  PubMed  Google Scholar 

  189. Bennett, G. J. & Xie, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107 (1988).

    Article  CAS  PubMed  Google Scholar 

  190. Kukkar, A., Singh, N. & Jaggi, A. S. Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats. J. Formos. Med. Assoc. 113, 921–928 (2014).

    Article  CAS  PubMed  Google Scholar 

  191. Shao, H. et al. Spinal SIRT1 activation attenuates neuropathic pain in mice. PLoS ONE 9, e100938 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Seltzer, Z., Dubner, R. & Shir, Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43, 205–218 (1990).

    Article  CAS  PubMed  Google Scholar 

  193. Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  194. Courteix, C., Eschalier, A. & Lavarenne, J. Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain 53, 81–88 (1993).

    Article  CAS  PubMed  Google Scholar 

  195. Cheng, W. et al. Resveratrol attenuates bone cancer pain through the inhibition of spinal glial activation and CX3CR1 upregulation. Fundam. Clin. Pharmacol. 28, 661–670 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by the Deutsche Forschungsgemeinschaft (SFB1039, Z01), and the LOEWE (Landes-Offensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz (State Initiative for the Development of Scientific and Economic Excellence)) Center for Translational Medicine and Pharmacology.

Author information

Authors and Affiliations

Authors

Contributions

All authors, wrote, edited and discussed content for the article. E.N. and E.R carried out the literature search.

Corresponding author

Correspondence to Gerd Geisslinger.

Ethics declarations

Competing interests

M.J.P. has been a consultant for Leo Pharma and Xellia Pharmaceuticals and was previously an employee of GlaxoSmithKline. G.G. is a member of the IMI (Innovative Medicine Initiative of the European Union) EuroPain collaboration, in which the following industry members are represented: Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Esteve, Grünenthal, Pfizer, UCB Pharma and Sanofi Aventis. In addition, G.G. has received honoraria as a speaker from Grünenthal, Mundipharma and Pfizer. He is a consultant for Abbvie and has received research funding in the form of a grant from Mundipharma.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Niederberger, E., Resch, E., Parnham, M. et al. Drugging the pain epigenome. Nat Rev Neurol 13, 434–447 (2017). https://doi.org/10.1038/nrneurol.2017.68

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2017.68

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing