Published Apr 21, 2015

Shiqin Xu  


Many factors have been identified contributing to the pathogenesis of pain, whereas we still cannot conquer the pain based on these findings suggesting that further studies are needed and other more potent mediators should be investigated. Epigenetics, in contrast to genetics, refers to the functionally relevant modifications to the genome that do not cause changes in underlying DNA sequence. These kinds of changes in gene expression or cellular phenotype regarded as landmarks of epigenetics are regulated by different types of modifications including gene methylation, histone acetylation, phosphorylation, imprinting and reprogramming etc. We, in this part (Part I), will review the general epigenetic modifications on molecular mediators on biological processes as the preface of the second part of the whole article (Part II will be available in the June issue of the journal). This general understanding of the epigenetic modification on the modulating factors that influence individual differences from pain sensitivity and responsiveness to analgesics possesses crucial clinical implications.



Epigenetics, Gene Modification, Nociception, Pathogenesis, Analgesia

Supporting Agencies

This work is supported by the National Natural Scientific Foundation of China (81271242, 81371248)

BASE Foundation from Bonoi Academy of Science and Education (BASE2013002B)

Nanjing Outstanding Young Scientists Grant (JQX12009)

1. Gilron I, Baron R, Jensen T. Neuropathic Pain: Principles of Diagnosis and Treatment. Mayo Clin Proc 2015; 90: 532-545.

2. Cohen SP. Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc 2015; 90: 284-299.

3. Mogil JS, Devor M. Introduction of pain genetics. The Genetics of Pain. IASP press. 2004. pp1-pp24.

4. Descalzi G, Ikegami D, Ushijima T, Nestler EJ, Zachariou V, Narita M. Epigenetic mechanisms of chronic pain. Trends Neurosci 2015; 38: 237-246.

5. Vikelis M, Mitsikostas DD. The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets 2007; 6: 251-257.

6. Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol 2011; 4: 379-388.

7. Tao YX. AMPA receptor trafficking in inflammation-induced dorsal horn central sensitization. Neurosci Bull 2012; 28: 111-120.

8. Bhangoo SK, Swanson GT. Kainate receptor signaling in pain pathways. Mol Pharmacol 2013; 83:307-315.

9. Montana MC, Gereau RW. Metabotropic glutamate receptors as targets for analgesia: antagonism, activation, and allosteric modulation. Curr Pharm Biotechnol 2011; 12: 1681-1688.

10. de Oliveira CM, Sakata RK, Issy AM, Gerola LR, Salomão R. Cytokines and pain. Rev Bras Anestesiol 2011; 61: 255-259.

11. Stemkowski PL, Smith PA. Sensory neurons, ion channels, inflammation and the onset of neuropathic pain. Can J Neurol Sci 2012; 39:416-435.

12. Andrade P, Visser-Vandewalle V, Hoffmann C, Steinbusch HW, Daemen MA, Hoogland G. Role of TNF-alpha during central sensitization in preclinical studies. Neurol Sci 2011; 32: 757-771.

13. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 2010;10: 985-1002.

14. del Rey A, Apkarian AV, Martina M, Besedovsky HO. Chronic neuropathic pain-like behavior and brain-borne IL-1beta. Ann N Y Acad Sci 2012; 1262: 101-107.

15. Wang F, Xu S, Shen X, Guo X, Peng Y, Yang J. Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity. Anesthesiology 2011;114: 643-659.

16. Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J. Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats. Pain 2010; 148: 275-283.

17. Kawabata A. Prostaglandin E2 and pain-an update. Biol Pharm Bull 2011; 34: 1170-1173.

18. Kanda H, Kobayashi K, Yamanaka H, Noguchi K. COX-1-dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons. Glia 2013;61: 943-956.

19. Levinson SR, Luo S, Henry MA. The role of sodium channels in chronic pain. Muscle Nerve 2012;46:155-165.

20. Gu C, Barry J. Function and mechanism of axonal targeting of voltage-sensitive potassium channels. Prog Neurobiol 2011; 94: 115-132.

21. Vink S, Alewood PF. Targeting voltage-gated calcium channels: developments in peptide and small-molecule inhibitors for the treatment of neuropathic pain. Br J Pharmacol 2012;167: 970-989.

22. Asiedu MN, Mejia G, Ossipov MK, Malan TP, Kaila K, Price TJ. Modulation of spinal GABAergic analgesia by inhibition of chloride extrusion capacity in mice. J Pain 2012; 13: 546-554.

23. Eto K, Ishibashi H, Yoshimura T, Watanabe M, Miyamoto A, Ikenaka K, Moorhouse AJ, Nabekura J. Enhanced GABAergic activity in the mouse primary somatosensory cortex is insufficient to alleviate chronic pain behavior with reduced expression of neuronal potassium-chloride cotransporter. J Neurosci 2012; 32: 16552-16559.

24. Cho H, Yang YD, Lee J, Lee B, Kim T, Jang Y, Back SK, Na HS, Harfe BD, Wang F, Raouf R, Wood JN, Oh U. The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons. Nat Neurosci 2012; 15: 1015-1021.

25. Pacheco Dda F, Pacheco CM, Duarte ID. Delta-Opioid receptor agonist SNC80 induces central antinociception mediated by Ca2+ -activated Cl- channels. J Pharm Pharmacol 2012; 64: 1084-1089.

26. Collom AB. Tears of the poppy; a review of the history of opium. J Kans Med Soc 1957; 58:614.

27. Coenen H. On the year of morphine discovery in Paderborn by Sertürner. Arch Pharm Ber Dtsch Pharm Ges 1954; 287: 165-180.

28. Middleton C, Harden J. Acquired pharmaco-dynamic opioid tolerance: a concept analysis. J Adv Nurs 2014; 70: 272-281.

29. Tawfic QA, Faris AS, Date RR. The dilemma of opioid-induced hyperalgesia and tolerance in chronic opioid therapy. Sultan Qaboos Univ Med J 2013; 13: 185-187.

30. Gonzalez-Nunez V, Jimenez González A, Barreto-Valer K, Rodríguez RE. In vivo regulation of the micro opioid receptor: role of the endogenous opioid agents. Mol Med 2013; 19: 7-17.

31. Mika J, Obara I, Przewlocka B. The role of nociceptin and dynorphin in chronic pain: implications of neuro-glial interaction. Neuropeptides 2011; 45: 247-261.

32. Romero TR, Guzzo LS, Duarte ID. Mu, delta, and kappa opioid receptor agonists induce peripheral antinociception by activation of endogenous noradrenergic system. J Neurosci Res 2012; 90: 1654-1661.

33. Park MH, Kieffer BL, Roberts AJ, Siggins GR, Moore SD. Kappa opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. J Pharmacol Exp Ther 2013; 346: 130-137.

34. Liu J, Ren Y, Li G, Liu ZL, Liu R, Tong Y, Zhang L, Yang K. GABAB receptors resist acute desensitization in both postsynaptic and presynaptic compartments of periaqueductal gray neurons. Neurosci Lett 2013; 543: 146-151.

35. Munro G, Hansen RR, Mirza NR. GABAA receptor modulation: Potential to deliver novel pain medicines? Eur J Pharmacol 2013; 716: 17-23.

36. Micó JA, Ardid D, Berrocoso E, Eschalier A. Antidepressants and pain. Trends Pharmacol Sci 2006; 27: 348-354.

37. Walker SM, Grafe M, Yaksh TL. Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity. Anesth Analg 2012; 115: 450-460.

38. Solanki SL, Bharti N, Batra YK, Jain A, Kumar P, Nikhar SA. The analgesic effect of intrathecal dexmedetomidine or clonidine, with bupivacaine, in trauma patients undergoing lower limb surgery: a randomised, double-blind study. Anaesth Intensive Care 2013; 41: 51-56.

39. Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, Petersen KL, Rowbotham MC, Campbell JN. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain 2012; 153: 1815-1823.

40. Salengros JC, Hecquet F, Touihri K, Sekkat J, Barvais L, Engelman E. Low-dose intravenous ketamine and clonidine for poor postoperative opioid responsiveness: a double blind randomized study. Acta Anaesthesiol Belg 2011; 62: 65-72.

41. Sarko J. Antidepressants, old and new. A review of their adverse effects and toxicity in overdose. Emerg Med Clin North Am 2000;18: 637-654.

42. Sacerdote P, Franchi S, Moretti S, Castelli M, Procacci P, Magnaghi V, Panerai AE. Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain. J Neuroimmune Pharmacol 2013; 8: 202-211.

43. Glocker EO, Kotlarz D, Klein C, Shah N, Grimbacher B. IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci 2011; 1246: 102-107.

44. Lantero A, Tramullas M, Díaz A, Hurlé MA. Transforming growth factor-beta in normal nociceptive processing and pathological pain models. Mol Neurobiol 2012; 45: 76-86.

45. Hübel K, Dale DC, Liles WC. Therapeutic use of cytokines to modulate phagocyte function for the treatment of infectious diseases: current status of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and interferon-gamma. J Infect Dis 2002; 185: 1490-1501.

46. Waddington CH. The epigenotype. Endeavour 1942; 1: 18-20.

47. Bird A. Perceptions of epigenetics. Nature 2007, 447: 396-398.

48. Crow M, Denk F, McMahon SB. Genes and epigenetic processes as prospective pain targets. Genome Med 2013; 5: 12.

49. Smith ZD, Meissner A. DNA methylation: Roles in mammalian development. Nat Rev Genet 2013; 14: 204-220.

50. Jakovcevski M, Akbarian S. Epigenetic mechanisms in neurological disease. Nat Med 2012; 18: 1194-1204.

51. Kelsey G, Feil R. New insights into establishment and maintenance of DNA methylation imprints in mammals. Philos Trans R Soc Lond B Biol Sci 2013; 368: 20110336.

52. Hackett JA, Surani MA. DNA methylation dynamics during the mammalian life cycle. Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20110328.

53. Malygin EG, Hattman S. DNA methyltransferases: mechanistic models derived from kinetic analysis. Crit Rev Biochem Mol Biol 2012; 47: 97-193.

54. Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: A structural perspective. Structure 2008; 16: 341-350.

55. Kowalski A, Palyga J. Linker histone subtypes and their allelic variants. Cell Biol Int 2012; 36: 981-996.

56. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: Establishment, regulation, and biological impact. Mol Cell 2012; 48: 491-507.

57. Lilja T, Heldring N, Hermanson O. Like a rolling histone: epigenetic regulation of neural stem cells and brain development by factors controlling histone acetylation and methylation. Biochim Biophys Acta 2013; 1830: 2354-2360.

58. Chen Y, Jie W, Yan W, Zhou K, Xiao Y. Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy. Crit Rev Eukaryot Gene Expr 2012; 22: 53-59.

59. Yokoyama A, Fujiki R, Ohtake F, Kato S. Regulated histone methyltransferase and demethylase complexes in the control of genes by nuclear receptors. Cold Spring Harb Symp Quant Biol 2011; 76: 165-173.

60. Gräff J, Tsai LH. Hisone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 2013; 14: 97-111.
61. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011; 21: 381-395.

62. Salvador LA, Luesch H. Discovery and mechanism of natural products as modulators of histone acetylation. Curr Drug Targets 2012;13: 1029-1047.

63. Tang J, Yan H, Zhuang S. Histone deacetylases as targets for treatment of multiple diseases. Clin Sci (Lond) 2013; 124: 651-662.

64. New M, Olzscha H, La Thangue NB. HDAC inhibitor-based therapies: can we interpret the code? Mol Oncol 2012; 6: 637-656.

65. Du HN. Transcription, DNA damage and beyond: the roles of histone ubiquitination and deubiquitination. Curr Protein Pept Sci 2012; 13: 447-466.

66. Trujillo KM, Tyler RK, Ye C, Berger SL, Osley MA. A genetic and molecular toolbox for analyzing histone ubiquitylation and sumoylation in yeast. Methods 2011; 54: 296-303.

67. Rossetto D, Avvakumov N, Côté J. Histone phosphorylation: A chromatin modification involved in diverse nuclear events. Epigenetics 2012; 7: 1098-1108.

68. Zhang Y. Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev 2003; 17: 2733-2740.

69. Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci USA 2003; 100: 13225-13230.

70. Martinez-Zamudio R, Ha HC. Histone ADP-ribosylation facilitates gene transcription by directly remodeling nucleosomes. Mol Cell Biol 2012; 32: 2490-2502.
How to Cite
Xu, S. (2015). Epigenetic Modification of Nociceptive Mediators: Implications for the Etiology of Neural Hypersensitivity (Part I). Science Insights, 12(1), 384–390. https://doi.org/10.15354/si.15.re015