Epigenetica van de farmacologie

van chronische pijn

Simon Pissens

Promotor: Prof. Dr. B. Morlion

∗ Epigenetica

∗ Epigenetica en de huidige pijnfarmaca

∗ Epigenetische farmaca

Inhoud

Epigenetica: Regulatie van genexpressie zonder veranderingen in de primaire DNA-sequentie

DNA-methylatie

Histone modificaties

Expressie van microRNA

∗ Prevalentie van 1 op 5

∗ Ontstaat frequent post-operatief

∗ Dysregulatie van de

transcriptie van bepaalde genen

∗ Centrale sensitisatie

Chronische pijn

∗ Farmacotherapie is een van de hoekstenen in de multimodale behandeling van chronische pijn

∗ Zeer verscheiden spectrum farmaca

∗ Opioïden

∗ NSAID’s

∗ Atypische analgetica:

∗ Antidepressiva (tricyclische en SNRI’s)

∗ VGCC α-2-δ-ligand modulatoren

∗ Ketamine

Farmacologie van chronische pijn

Opioïden en epigenetica

∗ ↓ bij neuropathische pijn

∗ Zhou et al.: DNA-methylatie thv proximale promotor MOR bij ratten met neuropathische pijn

∗ Hwang et al.: Lokale histone-deacetylisatie door MeCP2

∗ Uchida et al.: histone-hyperacetylisatie→ verhoogde transcriptie NRSF → histone-deacetylisatie thv MOR-promotor

Zhou X-L, Yu L-N, Wang Y, 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. Molecular Pain. 2014;10:51.Hwang CK, Song KY, Kim CS, Choi HS, Guo XH, Law PY, Wei LN, Loh HH. Evidence of endogenous mu opioid receptor regulation by epigenetic control of the promoters. Mol Cell Biol. 2007 ;27(13):4720-36. Uchida H, Ma L, Ueda H. Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain. J Neurosci. 2010 Mar 31;30(13):4806-14

Opioïden en epigenetica

∗ Chronisch opioïden: ↑ DNA-methylatie

∗ Wachman et al.: verhoogde DNA methylatie thvOPRM1 promotor ging gepaard met ernstiger beeld NAS

∗ Morfine: ↑MicroRNA’s→↓MOR

Wachman EM, Hayes MJ, Lester BM, Terrin N, Brown MS, Nielsen DA, Davis JM. Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome. J Pediatr. 2014 Sep;165(3):472-8

Ketamine en epigenetica

∗ Maternal deprived ratten

∗ ↑ HDAC thv nucleus accumbens

∗ 24 wijzigingen in microRNA thv hippocampus

∗ Réus et al.: Ketamine: ↓ HDAC thv n. accumbens

∗ O’Connor et al.: Ketamine: ging 11 wijzigingen in MiRNA tegen

Réus GZ, Abelaira HM, dos Santos MA, Carlessi AS, Tomaz DB, Neotti MV, Liranço JL, Gubert C, Barth M, Kapczinski F, Quevedo J. Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors. Behav Brain Res. 2013 Nov 1;256:451-6O'Connor RM, Grenham S, Dinan TG, Cryan JF. MicroRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol. 2013 Sep;16(8):1885-92.

SNRI’s & TCA’s en epigenetica

∗ Ookubo et al.: clomipramine en duloxetine: effect op HDAC & histone-acetylisatie in muizenhersenen

∗ Imipramine: ↓ HDAC thv n. accumbens (zoals ketamine)

∗ Imipramine (in vitro): ↓ HDAC thv NR2B-gen, NMDA-subeenheid

Ookubo M, Kanai H, Aoki H, Yamada N. Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes. J Psychiatr Res. 2013 ;47(9):1204-14

NSAID’s en epigenetica

∗ Veel interesse voor mogelijks protectief effect maliginiteiten

∗ Zhu et al.: ↑ COX-2 door histone-acetylisatie door p300, een enzyme met een HAT functie bij ratten met neuropathische pijn

Zhu XY, Huang CS, Li Q, Chang RM, Song ZB, Zou WY, Guo QL. p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI). Mol Pain. 2012 Nov 23;8:84.

α-2-δ-ligand modulatoren en epigenetica

∗ Eyal et al.: in-vitro geen HDAC inhibitie door gabapentine

∗ Favereaux et al.: Ratten met neuropathische pijn: ↓miRNA-103 en ↑ Cav1.2 mRNA

∗ Spinale toediening miRNA-103 zorgde voor ↓ Cav1.2 mRNA en ↓ hypersensitiviteit

Favereaux A, Thoumine O, Bouali-Benazzouz R, Roques V, Papon MA, Salam SA, Drutel G, Léger C, Calas A, Nagy F, Landry M. Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. EMBO J. 2011 Jul 29;30(18):3830-41.Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia. 2004 Jul;45(7):737-44.

∗ DNMT-inhibitoren

∗ HDAC-inhibitoren

∗ MicroRNA

Epigenetische farmaca

∗ Omkeren van hypermethylatie van tumor-suppressor-genen

∗ 5-azacytidine goedgekeurd door FDA in behandeling van myelodysplasie

∗ Wang et al.: spinale toediening 5-acacytidine “post-op” (d3-14) bij ratten met neuropathische pijn

∗ Vermindering DNA hypermethylatie en ↓MeCP2

∗ Vermindering van mechanische allodynie en thermale hyperalgesie

DNMT inhibitoren

Wang Y, Liu C, Guo QL, Yan JQ, Zhu XY, Huang CS, Zou WY. 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. 2011 Oct 18;1418:64-9.

∗ Verhogen expressie tumor-suppressor genen

∗ Goedgekeurd door FDA tbv hematologische maligniteiten en solide tumoren

∗ Bai et al. verbetering inflammatoire pijn bij muizen door spinale toediening HDAC inhibitoren (waaronder VPA)

∗ Denk et al.: effect op neuropathische pijn bij ratten met toediening HDAC inhibitor enkel indien “preop” reeds gestart

HDAC inhibitoren

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. 2010 Sep 7;6:51Denk F, Huang W, Sidders B, Bithell A, Crow M, Grist J, Sharma S, Ziemek D, Rice AS, Buckley NJ, McMahon SB. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain. 2013 Sep;154(9):1668-79.

∗ Mogelijkheid specifieke “pathways” te beïnvloeden

∗ Sakai et al.: ↓ expressie van MiRNA-7a thv ganglion spinale bij ratten in latere fase (d7-14) van neuropathische pijn

∗ ↓MiRNA-7a ging gepaard met ↑ β2 subeenheid VG Na kanaal

∗ ↑MiRNA-7a dmv virale vector kon zelfs bij laattijdige toediening effect bekomen op neuropathische pijn

MicroRNA

Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H. miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability. Brain. 2013 Sep;136(Pt 9):2738-50.

∗ Epigenetica speelt een belangrijke rol in zowel het ontstaan als het onderhoud van chronische pijn

∗ Epigenetische mechanismen bieden een verklaring waarom sommige farmaca wel en andere niet effectief zijn bij bepaalde vormen van chronische pijn

∗ Sommige farmaca oefenen zelf een effect uit op de epigenetische regulatie, de relevantie hiervan is niet steeds duidelijk: aanvullende onderzoek mbt chronische pijn is vereist

∗ Bepaalde epigenetische farmaca lijken veelbelovend vanuit therapeutisch opzicht

Conclusie

∗ Descalzi G, Ikegami D, Ushijima T, Nestler E, Zachariou V, Narita M. Epigenetic Mechanisms of Chronic Pain. Trends in neurosciences. 2015;38(4):237-246.∗ Doehring A, Oertel BG, Sittl R, Lötsch J. Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain. Pain. 2013 Jan;154(1):15-23.∗ Zhou X-L, Yu L-N, Wang Y, 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. Molecular

Pain. 2014;10:51.∗ Stone LS, Szyf M. The emerging field of pain epigenetics. Pain. 2013 Jan;154(1):1-2∗ Obara I, Parkitna JR, Korostynski M, Makuch W, Kaminska D, Przewlocka B, Przewlocki R. Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and

inflammatory pain. Pain. 2009 Feb;141(3):283-91.∗ Muñoa I, Urizar I, Casis L, Irazusta J, Subirán. The Epigenetic Regulation of the Opioid System: New Individualized Prompt Prevention and Treatment Strategies. J Cell Biochem. 2015 Nov;116(11):2419-26. ∗ Uchida H, Ma L, Ueda H. Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain. J Neurosci. 2010 Mar 31;30(13):4806-14∗ Géranton SM. Targeting epigenetic mechanisms for pain relief. Curr Opin Pharmacol. 2012 Feb;12(1):35-41 ∗ Réus GZ, Abelaira HM, dos Santos MA, Carlessi AS, Tomaz DB, Neotti MV, Liranço JL, Gubert C, Barth M, Kapczinski F, Quevedo J. Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation

induced by maternal deprivation and are critical for associated behaviors. Behav Brain Res. 2013 Nov 1;256:451-6∗ Ookubo M, Kanai H, Aoki H, Yamada N. Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes. J Psychiatr Res. 2013 Sep;47(9):1204-14 ∗ O'Connor RM, Grenham S, Dinan TG, Cryan JF. MicroRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol.

2013 Sep;16(8):1885-92.∗ 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). 2014

Jun;37(3):167-78∗ Fitzsimmons BL, Zattoni M, Svensson CI, Steinauer J, Hua X-Y, Yaksh TL. Role of spinal p38α and β MAPK in inflammatory hyperalgesia and spinal COX-2 expression. Neuroreport. 2010;21(4):313-317.∗ Zhu XY, Huang CS, Li Q, Chang RM, Song ZB, Zou WY, Guo QL. p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI). Mol Pain.

2012 Nov 23;8:84.∗ Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014 Jun;8(2):143-51. ∗ Denk F, McMahon SB, Tracey I. Pain vulnerability: a neurobiological perspective. Nat Neurosci. 2014 Feb;17(2):192-200.∗ Denk F, McMahon SB. Chronic pain: emerging evidence for the involvement of epigenetics. Neuron. 2012 Feb 9;73(3):435-44∗ Denk F, Huang W, Sidders B, Bithell A, Crow M, Grist J, Sharma S, Ziemek D, Rice AS, Buckley NJ, McMahon SB. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain. 2013

Sep;154(9):1668-79.∗ Crow M, Denk F, McMahon SB. Genes and epigenetic processes as prospective pain targets. Genome Med. 2013 Feb 15;5(2):12.∗ Buchheit T, Van de Ven T, Shaw A. Epigenetics and the transition from acute to chronic pain. Pain Med. 2012 Nov;13(11):1474-90∗ American Society of Anesthesiologists Task Force on Chronic Pain Management; American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the

American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010 Apr;112(4):810-33∗ Hashmi JA, Baliki MN, Huang L, Baria AT, Torbey S, Hermann KM, Schnitzer TJ, Apkarian AV. Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain. 2013

Sep;136(Pt 9):2751-68∗ Kirkpatrick DR, McEntire DM, Hambsch ZJ, Kerfeld MJ, Smith TA, Reisbig MD, Youngblood CF, Agrawal DK. Therapeutic Basis of Clinical Pain Modulation. Clin Transl Sci. 2015 Dec;8(6):848-56

Referenties

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pain. EMBO J. 2011 Jul 29;30(18):3830-41.∗ Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia. 2004 Jul;45(7):737-44.∗ Jones CK, Eastwood BJ, Need AB, Shannon HE. Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and

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chronic constriction injury. Brain Res. 2011 Oct 18;1418:64-9.∗ Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H. miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability. Brain. 2013 Sep;136(Pt 9):2738-50.∗ Kynast KL, Russe OQ, Möser CV, Geisslinger G, Niederberger E. Modulation of central nervous system-specific microRNA-124a alters the inflammatory response in the formalin test in mice. Pain. 2013 Mar;154(3):368-76∗ Chen HP, Zhou W, Kang LM, Yan H, Zhang L, Xu BH, Cai WH. Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury. Neurochem Res. 2014 Jan;39(1):76-

83.

Referenties