Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain

Abstract

Knowing that expression of metabotropic glutamate 2 (mGlu2) receptors in the dorsal root ganglia is regulated by acetylation mechanisms, we examined the effect of two selective and chemically unrelated histone deacetylase (HDAC) inhibitors, N- (2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275) and suberoylanilide hydroamic acid (SAHA), in a mouse model of persistent inflammatory pain. Although a single subcutaneous injection of MS-275 (3 mg/kg) or SAHA (5-50 mg/kg) was ineffective, a 5-day treatment with either of the two HDAC inhibitors substantially reduced the nociceptive response in the second phase of the formalin test, which reflects the development of central sensitization in the dorsal horn of the spinal cord. Analgesia was abrogated by a single injection of the mGlu2/3 receptor antagonist (␣S)-␣-amino-␣-[(1S,2S)-2-carboxycyclopropyl]-9H-xantine-9-propanoic acid (LY341495; 1 mg/kg, i.p.), which was inactive per se. Both MS-275 and SAHA upregulated the expression of mGlu2 receptors in the dorsal root ganglion (DRG) and spinal cord under conditions in which they caused analgesia, without changing the expression of mGlu1a, mGlu4, or mGlu5 receptors. Induction of DRG mGlu2 receptors in response to SAHA was associated with increased acetylation of p65/RelA on lysine 310, a process that enhances the transcriptional activity of p65/RelA at nuclear factor-B-regulated genes. Transcription of the mGlu2 receptor gene is known to be activated by p65/RelA in DRG neurons. We conclude that HDAC inhibition produces analgesia by up-regulating mGlu2 receptor expression in the DRG, an effect that results from the amplification of NF-B transcriptional activity. These data provide the first evidence that HDAC inhibitors cause analgesia and suggest that HDACs are potential targets for the epigenetic treatment of pain.Histone deacetylase (HDAC) inhibitors are known to modulate gene expression by increasing acetylation of histone proteins, thus remodeling chromatin structure (Strahl and Allis, 2000). Eighteen HDAC isoenzymes have been identified and divided into four classes based on their homology to yeast deacetylase proteins. Class I HDACs include the HDAC1, -2, -3, and -8 isoforms. These enzymes are ubiquitously expressed and have a predominant nuclear localization. Class II HDACs, which include HDAC4, -5, -6, -7, -9, and -10, are cytosolic enzymes and have a more restricted tissue pattern of expression. Class III HDACs include sirtuins, whereas HDAC11 is the only member of class IV HDAC and shares properties of both class I and II HDACs (Xu et al., 2007;Yang and Seto, 2007).In addition to histones, a number of nonhistone proteins, mainly transcription factors, are regulated by acetylation and are specifically targeted by HDACs (Spange et al., 2009). In particular, members of the nuclear factor-B (NF-B) family of transcription factors are known to be regulated by reversible acetylation (Chen et al., 2001). The NF-B/Rel family consists of p50, p52, p65/RelA, c-Rel, and RelB, which Arti...

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

“…Results from transgenic mice point to mGlu2 receptors mediating the effects of the mixed agonist in models of schizophrenia (Fell et al, 2008;Woolley et al, 2008), whereas human tissue studies favor a role for mGlu3 receptors in psychiatric disease (Corti et al, 2007a;Harrison et al, 2008). The mGlu2 receptors also appear to mediate the analgesic effects of mixed agonists (Chiechio et al, 2009), whereas mGlu3 receptors mediate their neuroprotective effects (Corti et al, 2007b), and their anxiolytic activity appears to be mediated by both group II receptors (Linden et al, 2005). However, the initial behavioral observation that the insensitive B&K:Wi strain shows a more anxiety-like profile suggests that the lack of mGlu2 receptors may be one of the factors leading to an anxious phenotype and may suggest that mGlu2 receptors mediate at least some of the anxiolytic actions of mixed mGlu2/3 agonists reported in the clinic (Grillon et al, 2003;Dunayevich et al, 2008), although mGlu2 KO mice are not reported to have an anxious phenotype (Linden et al, 2005).…”

L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors

“…Recent evidence suggests that the acetylating agent L-acetylcarnitine (LAC), a drug marketed for the treatment of neuropathic pain (9), causes analgesia increasing type 2 metabotropic glutamate (mGlu2) expression via an epigenetic mechanism shared by HDAC inhibitors (10)(11)(12). mGlu2 and its cognate receptor, mGlu3, are coupled to Gi/Go proteins and are preferentially (albeit not exclusively) localized in the preterminal region of axons, where they negatively modulate neurotransmitter release (13).…”

Molecular Signatures of Chronic Pain Subtypes

“…TSA produces analgesia in animal models with an associated decrease in expression of transient receptor potential type-1 cation channel (TRPV1) and protein kinase Ce [157]. SAHA reduces the nociceptive response of animals during the second phase of the formalin test [154]. These drugs increase acetylation of the transcription factor p65/Re1A, which enhances gene expression of the metabotrobic glutamate receptors (mGlu2) in dorsal root ganglia neurons.…”

“…In neurodegenerative disease, HDACis have been evaluated secondary to their ability to induce neural growth and to improve memory [153]. HDACis have also demonstrated evidence for analgesia in both inflammatory and neuropathic pain [151,154,155]. The clinical effect of many of these drugs is thought to be partially attributed to reduced production of inflammatory cytokines such as TNF-a and IL-1b [156].…”