Abstract
Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show here that in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
MacDonald, J.L. & Roskams, A.J. Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation. Prog. Neurobiol. 88, 170–183 (2009).
Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).
Strahl, B.D. & Allis, C.D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Urdinguio, R.G., Sanchez-Mut, J.V. & Esteller, M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8, 1056–1072 (2009).
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).
Guan, J.S. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55–60 (2009).
Tsankova, N., Renthal, W., Kumar, A. & Nestler, E.J. Epigenetic regulation in psychiatric disorders. Nat. Rev. Neurosci. 8, 355–367 (2007).
Grayson, D.R., Kundakovic, M. & Sharma, R.P. Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders? Mol. Pharmacol. 77, 126–135 (2010).
Reichling, D.B. & Levine, J.D. Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 32, 611–618 (2009).
Campbell, J.N. & Meyer, R.A. Mechanisms of neuropathic pain. Neuron 52, 77–92 (2006).
Scascighini, L. & Sprott, H. Chronic nonmalignant pain: a challenge for patients and clinicians. Nat. Clin. Pract. Rheumatol. 4, 74–81 (2008).
Costigan, M., Scholz, J. & Woolf, C.J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009).
Milligan, E.D. & Watkins, L.R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 10, 23–36 (2009).
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).
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).
Uchida, H., Ma, L. & Ueda, H. Epigenetic gene silencing underlies C-fiber dysfunctions in neuropathic pain. J. Neurosci. 30, 4806–4814 (2010).
Porreca, F., Ossipov, M.H. & Gebhart, G.F. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319–325 (2002).
Fields, H. State-dependent opioid control of pain. Nat. Rev. Neurosci. 5, 565–575 (2004).
Zhang, L. & Hammond, D.L. Cellular basis for opioid potentiation in the rostral ventromedial medulla of rats with persistent inflammatory nociception. Pain 149, 107–116 (2010).
Zhang, Z. & Pan, Z.Z. Synaptic mechanism for functional synergism between delta- and mu-opioid receptors. J. Neurosci. 30, 4735–4745 (2010).
Zucker, R.S. & Regehr, W.G. Short-term synaptic plasticity. Annu. Rev. Physiol. 64, 355–405 (2002).
Soghomonian, J.J. & Martin, D.L. Two isoforms of glutamate decarboxylase: why? Trends Pharmacol. Sci. 19, 500–505 (1998).
Tian, N. et al. The role of the synthetic enzyme GAD65 in the control of neuronal γ-aminobutyric acid release. Proc. Natl. Acad. Sci. USA 96, 12911–12916 (1999).
Finnin, M.S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999).
Chawla, S., Vanhoutte, P., Arnold, F.J., Huang, C.L. & Bading, H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159 (2003).
Kurdistani, S.K. & Grunstein, M. Histone acetylation and deacetylation in yeast. Nat. Rev. Mol. Cell Biol. 4, 276–284 (2003).
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).
Pan, Z.Z., Tershner, S.A. & Fields, H.L. Cellular mechanism for anti-analgesic action of agonists of the κ-opioid receptor. Nature 389, 382–385 (1997).
Pan, Z.Z. Mu-opposing actions of the κ-opioid receptor. Trends Pharmacol. Sci. 19, 94–98 (1998).
Blackburn-Munro, G. & Blackburn-Munro, R.E. Chronic pain, chronic stress and depression: coincidence or consequence? J. Neuroendocrinol. 13, 1009–1023 (2001).
Duric, V. et al. A negative regulator of MAP kinase causes depressive behavior. Nat. Med. 16, 1328–1332 (2010).
Watkins, L.R. & Maier, S.F. The pain of being sick: implications of immune-to-brain communication for understanding pain. Annu. Rev. Psychol. 51, 29–57 (2000).
Watkins, L.R. & Maier, S.F. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol. Rev. 82, 981–1011 (2002).
Lacroix-Fralish, M.L., Ledoux, J.B. & Mogil, J.S. The Pain Genes Database: an interactive web browser of pain-related transgenic knockout studies. Pain 131, 3.e1–3.e4 (2007).
Patel, A.B., de Graaf, R.A., Martin, D.L., Battaglioli, G. & Behar, K.L. Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. J. Neurochem. 97, 385–396 (2006).
Moore, K.A. et al. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J. Neurosci. 22, 6724–6731 (2002).
Munro, G., Ahring, P.K. & Mirza, N.R. Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets. Trends Pharmacol. Sci. 30, 453–459 (2009).
Knabl, J. et al. Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451, 330–334 (2008).
Kubo, K. et al. Thermal hyperalgesia via supraspinal mechanisms in mice lacking glutamate decarboxylase 65. J. Pharmacol. Exp. Ther. 331, 162–169 (2009).
Vit, J.P. et al. Adenovector GAD2 gene delivery into the rat trigeminal ganglion produces orofacial analgesia. Mol. Pain 5, 42 (2009).
Pan, Z.Z., Williams, J.T. & Osborne, P.B. Opioid actions on single nucleus raphe magnus neurons from rat and guinea pig in vitro. J. Physiol. (Lond.) 427, 519–532 (1990).
Gilbert, A.K. & Franklin, K.B. GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM). Dose-response analysis of nociception and neurological deficits. Pain 90, 25–36 (2001).
Heinricher, M.M. & Kaplan, H.J. GABA-mediated inhibition in rostral ventromedial medulla: role in nociceptive modulation in the lightly anesthetized rat. Pain 47, 105–113 (1991).
Ren, W. & Neugebauer, V. Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1. Mol. Pain 6, 93 (2010).
Apkarian, A.V., Baliki, M.N. & Geha, P.Y. Towards a theory of chronic pain. Prog. Neurobiol. 87, 81–97 (2009).
Woolf, C.J. & Hashmi, M. Use and abuse of opioid analgesics: potential methods to prevent and deter non-medical consumption of prescription opioids. Curr. Opin. Investig. Drugs 5, 61–66 (2004).
Doehring, A., Geisslinger, G. & Lotsch, J. Epigenetics in pain and analgesia: an imminent research field. Eur. J. Pain 15,11–16 (2010).
Roozendaal, B. et al. Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification. J. Neurosci. 30, 5037–5046 (2010).
Ma, J., Zhang, Y., Kalyuzhny, A.E. & Pan, Z.Z. Emergence of functional delta-opioid receptors induced by long-term treatment with morphine. Mol. Pharmacol. 69, 1137–1145 (2006).
Ma, J. & Pan, Z.Z. Contribution of brainstem GABA(A) synaptic transmission to morphine analgesic tolerance. Pain 122, 163–173 (2006).
Acknowledgements
This work was supported by US National Institutes of Health National Institute on Drug Abuse grants DA023069 and DA027541. We thank L. Gao of Baylor College of Medicine for his generous gifts of GAD67 primers.
Author information
Authors and Affiliations
Contributions
Z.Z. designed the studies, performed most of the experiments and wrote a draft manuscript. Y.-Q.C., F.Z. and B.B. conducted some of the molecular and behavioral experiments. Z.Z.P. was involved in the overall designs of the project and individual experiments, the data analyses and the writing of the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–4 and Supplementary Methods (PDF 1460 kb)
Rights and permissions
About this article
Cite this article
Zhang, Z., Cai, YQ., Zou, F. et al. Epigenetic suppression of GAD65 expression mediates persistent pain. Nat Med 17, 1448–1455 (2011). https://doi.org/10.1038/nm.2442
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2442
This article is cited by
-
Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain
Molecular Medicine (2023)
-
Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice
Nature Communications (2022)
-
SAHA Inhibits Somatic Hyperalgesia Induced by Stress Combined with Orofacial Inflammation Through Targeting Different Spinal 5-HT Receptor Subtypes
Neurochemical Research (2022)
-
α6GABAA Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia
Neurotherapeutics (2021)
-
Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity
Molecular Neurobiology (2021)