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Central Endothelin-1 Confers Analgesia by Triggering Spinal Neuronal Histone Deacetylase 5 (HDAC5) Nuclear Exclusion in Peripheral Neuropathic Pain in Mice

  • Pan Gu
    Affiliations
    Department of Anaesthesiology, The University of Hong Kong, HKSAR, China

    Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China

    Department of Anaesthesiology, The University of Hong Kong-Shenzhen Hospital, Guangdong province, China
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  • Tingting Fan
    Affiliations
    Department of Anaesthesiology, The University of Hong Kong, HKSAR, China

    Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China
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  • Stanley Sau Ching Wong
    Affiliations
    Department of Anaesthesiology, The University of Hong Kong, HKSAR, China

    Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China
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  • Zhiqiang Pan
    Affiliations
    Jiangsu Province Key Laboratory of Anaesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
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  • Wai Lydia Tai
    Affiliations
    Department of Anaesthesiology, The University of Hong Kong, HKSAR, China

    Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China

    Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
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  • Sookja Kim Chung
    Affiliations
    Macau University of Science and Technology, Taipa, Macau

    School of Biomedical Sciences, The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong
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  • Chi Wai Cheung
    Correspondence
    Address reprint requests to Chi Wai Cheung, MD, Department of Anaesthesiology, The University of Hong Kong, Room 424, 4/F, Block K, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, China..
    Affiliations
    Department of Anaesthesiology, The University of Hong Kong, HKSAR, China

    Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China

    Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, HKSAR, China

    Department of Anaesthesiology, The University of Hong Kong-Shenzhen Hospital, Guangdong province, China
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Published:January 06, 2021DOI:https://doi.org/10.1016/j.jpain.2020.12.004

      Abstract

      The rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant). Notably, ET-1 administration increased spinal glutamate acid decarboxylases (GAD65/67) expression via initiating HDAC5 nuclear exportation and increased the acetylation of histone 3 at lysine 9 (Acetyl-H3K9) in the promotor regions of spinal Gad1 and Gad2 genes. This was reversed by blocking endothelin A receptor function or by inhibiting the spinal neuronal nuclear exportation of HDAC5. Therefore, inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain.

      Perspective

      Neuropathic pain is intractable in a clinical setting, and epigenetic regulation is considered to contribute to this processing. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain.

      Key words

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      References

        • Backs J
        • Song K
        • Bezprozvannaya S
        • Chang S
        • Olson EN.
        CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy.
        J Clin Invest. 2006; 116: 1853-1864
        • Barr TP
        • Hrnjic A
        • Khodorova A
        • Sprague JM
        • Strichartz GR
        Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity.
        Pain. 2014; 155: 1091-1101
        • Bossuyt J
        • Chang CW
        • Helmstadter K
        • Kunkel MT
        • Newton AC
        • Campbell KS
        • Martin JL
        • Bossuyt S
        • Robia SL
        • Bers DM.
        Spatiotemporally distinct protein kinase D activation in adult cardiomyocytes in response to phenylephrine and endothelin.
        J Biol Chem. 2011; 286: 33390-33400
        • Chawla S
        • Vanhoutte P
        • Arnold FJ
        • Huang CL
        • Bading H.
        Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5.
        J Neurochem. 2003; 85: 151-159
        • Cunha TM
        • Verri Jr., WA
        • Vivancos GG
        • Moreira IF
        • Reis S
        • Parada CA
        • Cunha FQ
        • Ferreira SH
        An electronic pressure-meter nociception paw test for mice.
        Braz J Med Biol Res. 2004; 37: 401-407
        • Descalzi G
        • Ikegami D
        • Ushijima T
        • Nestler EJ
        • Zachariou V
        • Narita M.
        Epigenetic mechanisms of chronic pain.
        Trends Neurosci. 2015; 38: 237-246
        • Ellis JJ
        • Valencia TG
        • Zeng H
        • Roberts LD
        • Deaton RA
        • Grant SR.
        CaM kinase IIdeltaC phosphorylation of 14-3-3beta in vascular smooth muscle cells: activation of class II HDAC repression.
        Mol Cell Biochem. 2003; 242: 153-161
        • Finnerup NB
        • Attal N
        • Haroutounian S
        • McNicol E
        • Baron R
        • Dworkin RH
        • Gilron I
        • Haanpaa M
        • Hansson P
        • Jensen TS
        • Kamerman PR
        • Lund K
        • Moore A
        • Raja SN
        • Rice AS
        • Rowbotham M
        • Sena E
        • Siddall P
        • Smith BH
        • Wallace M.
        Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.
        Lancet. Neurol. 2015; 14: 162-173
        • Gokin AP
        • Fareed MU
        • Pan HL
        • Hans G
        • Strichartz GR
        • Davar G.
        Local injection of endothelin-1 produces pain-like behavior and excitation of nociceptors in rats.
        J Neurosci. 2001; 21: 5358-5366
        • Grozinger CM
        • Schreiber SL.
        Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization.
        Proc Natl Acad Sci U S A. 2000; 97: 7835-7840
        • Gu P
        • Pan Z
        • Wang XM
        • Sun L
        • Tai LW
        • Cheung CW.
        Histone deacetylase 5 (HDAC5) regulates neuropathic pain through SRY-related HMG-box 10 (SOX10)-dependent mechanism in mice.
        Pain. 2018; 159: 526-539
        • Ha CH
        • Kim JY
        • Zhao J
        • Wang W
        • Jhun BS
        • Wong C
        • Jin ZG.
        PKA phosphorylates histone deacetylase 5 and prevents its nuclear export, leading to the inhibition of gene transcription and cardiomyocyte hypertrophy.
        Proc Natl Acad Sci U S A. 2010; 107: 15467-15472
        • Hasue F
        • Kuwaki T
        • Yamada H
        • Fukuda Y
        • Shimoyama M.
        Inhibitory actions of endothelin-1 on pain processing.
        J Cardiovasc Pharmacol. 2004; 44: S318-S320
        • Heinke B
        • Ruscheweyh R
        • Forsthuber L
        • Wunderbaldinger G
        • Sandkuhler J.
        Physiological, neurochemical and morphological properties of a subgroup of GABAergic spinal lamina II neurones identified by expression of green fluorescent protein in mice.
        J Physiol. 2004; 560: 249-266
        • Hung VK
        • Chen SM
        • Tai LW
        • Chen AY
        • Chung SK
        • Cheung CW.
        Over-expression of endothelin-1 in astrocytes, but not endothelial cells, ameliorates inflammatory pain response after formalin injection.
        Life Sci. 2012; 91: 618-622
        • Hung VK
        • Tai LW
        • Luo X
        • Wang XM
        • Chung SK
        • Cheung CW.
        Targeted overexpression of astrocytic endothelin-1 attenuates neuropathic pain by upregulating spinal excitatory amino acid transporter-2.
        J Mol Neurosci. 2015; 57: 90-96
        • Hung VK
        • Tai LW
        • Qiu Q
        • Luo X
        • Wong KL
        • Chung SK
        • Cheung CW.
        Over-expression of astrocytic ET-1 attenuates neuropathic pain by inhibition of ERK1/2 and Akt(s) via activation of ETA receptor.
        Mol Cell Neurosci. 2014; 60: 26-35
        • Kamei J
        • Hitosugi H
        • Kawashima N
        • Misawa M
        • Kasuya Y.
        Antinociceptive effects of intrathecally administered endothelin-1 in mice.
        Neurosci Lett. 1993; 153: 69-72
        • Khodorova A
        • Navarro B
        • Jouaville LS
        • Murphy JE
        • Rice FL
        • Mazurkiewicz JE
        • Long-Woodward D
        • Stoffel M
        • Strichartz GR
        • Yukhananov R
        • Davar G.
        Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury.
        Nat Med. 2003; 9: 1055-1061
        • Lemercier C
        • Verdel A
        • Galloo B
        • Curtet S
        • Brocard MP
        Khochbin S. mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity.
        J Biolog Chem. 2000; 275: 15594-15599
        • Li S
        • Yang C
        • Zhang L
        • Gao X
        • Wang X
        • Liu W
        • Wang Y
        • Jiang S
        • Wong YH
        • Zhang Y
        • Liu K.
        Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling.
        Proc Natl Acad Sci U S A. 2016; 113: 1937-1942
        • Lo AC
        • Chen AY
        • Hung VK
        • Yaw LP
        • Fung MK
        • Ho MC
        • Tsang MC
        • Chung SS
        • Chung SK
        Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet.
        J Cereb Blood Flow Metab. 2005; 25: 998-1011
        • Lu J
        • McKinsey TA
        • Nicol RL
        • Olson EN
        Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases.
        Proc Natl Acad Sci U S A. 2000; 97: 4070-4075
        • Lu J
        • McKinsey TA
        • Zhang CL
        • Olson EN.
        Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases.
        Mol Cell. 2000; 6: 233-244
        • McKinsey TA
        • Zhang CL
        • Lu J
        • Olson EN.
        Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation.
        Nature. 2000; 408: 106-111
        • Meisner JG
        • Marsh AD
        • Marsh DR.
        Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury.
        J Neurotrauma. 2010; 27: 729-737
        • Mihaylova MM
        • Vasquez DS
        • Ravnskjaer K
        • Denechaud PD
        • Yu RT
        • Alvarez JG
        • Downes M
        • Evans RM
        • Montminy M
        • Shaw RJ.
        Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis.
        Cell. 2011; 145: 607-621
        • Miska EA
        • Karlsson C
        • Langley E
        • Nielsen SJ
        • Pines J
        • Kouzarides T.
        HDAC4 deacetylase associates with and represses the MEF2 transcription factor.
        EMBO J. 1999; 18: 5099-5107
        • Mule NK
        • Singh JN
        • Shah KU
        • Gulati A
        • Sharma SS.
        Endothelin-1 decreases excitability of the dorsal root ganglion neurons via ETB receptor.
        Mol Neurobiol. 2018; 55: 4297-4310
        • Ooi JY
        • Tuano NK
        • Rafehi H
        • Gao XM
        • Ziemann M
        • Du XJ
        El-Osta A. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes.
        Epigenetics. 2015; 10: 418-430
        • Pan Z
        • Shan Q
        • Gu P
        • Wang XM
        • Tai LW
        • Sun M
        • Luo X
        • Sun L
        • Cheung CW
        miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis.
        J Neuroinflammation. 2018; 15: 29
        • Seltzer Z
        • Dubner R
        • Shir Y.
        A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury.
        Pain. 1990; 43: 205-218
        • Shen X
        • Liu Y
        • Xu S
        • Zhao Q
        • Wu H
        • Guo X
        • Shen R
        • Wang F.
        Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain.
        Pharmacol Rep. 2014; 66: 49-55
        • Sivilotti L
        • Woolf CJ.
        The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord.
        J Neurophysiol. 1994; 72: 169-179
        • Tai LW
        • Hung VK
        • Mei W
        • Qiu Q
        • Chung SK
        • Cheung CW.
        Effects of repeated central administration of endothelin type A receptor antagonist on the development of neuropathic pain in rats.
        BioMed Res Int. 2013; 2013529871
        • Tai LW
        • Pan Z
        • Sun L
        • Li H
        • Gu P
        • Wong SSC
        • Chung SK
        • Cheung CW.
        Suppression of Pax2 attenuates allodynia and hyperalgesia through ET-1-ETAR-NFAT5 signaling in a rat model of neuropathic pain.
        Neuroscience. 2018; 384: 139-151
        • Todd AJ
        • Watt C
        • Spike RC
        • Sieghart W.
        Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord.
        J Neurosci. 1996; 16: 974-982
        • van der Linden AM
        • Nolan KM
        • Sengupta P.
        KIN-29 SIK regulates chemoreceptor gene expression via an MEF2 transcription factor and a class II HDAC.
        EMBO J. 2007; 26: 358-370
        • Vega RB
        • Harrison BC
        • Meadows E
        • Roberts CR
        • Papst PJ
        • Olson EN
        • McKinsey TA.
        Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5.
        Mol Cell Biol. 2004; 24: 8374-8385
        • Weeks KL
        • Ranieri A
        • Karaś A
        • Bernardo BC
        • Ashcroft AS
        • Molenaar C
        • McMullen JR
        • Avkiran M.
        β-Adrenergic stimulation induces histone deacetylase 5 (HDAC5) nuclear accumulation in cardiomyocytes by B55α-PP2A-Mediated dephosphorylation.
        J Am Heart Assoc. 2017; 6e004861
        • Zhang Z
        • Cai YQ
        • Zou F
        • Bie B
        • Pan ZZ.
        Epigenetic suppression of GAD65 expression mediates persistent pain.
        Nat Med. 2011; 17: 1448-1455