The Nociceptive Nature of Histone Deacetylase
A trio of studies presented at the 44th annual meeting of the Society for Neuroscience, held November 15-19 in Washington, DC, US, adds to a growing body of literature suggesting that blocking activity of histone deacetylases (HDACs) can offer relief from various types of pain (see PRF related news story; PRF related news story). Key epigenetic regulators, HDACs remove lysine residues from histones, allowing the histones to bind more tightly to DNA and promoting the formation of condensed chromatin that is associated with transcriptional repression.
Relief by HDAC reduction
At a poster session on Tuesday afternoon, November 18, Casey Ligon from the University of Oklahoma, Oklahoma City, US, presented data on the role of histone deacetylation in somatic allodynia and visceral hyperalgesia (Tran et al., 2014). Prior work from this group found that these symptoms could be induced in rats by raising corticosterone levels in the central amygdala, modeling the stress-induced exacerbation of irritable bowel syndrome (IBS).
In the new study, rats received stereotaxic implants of corticosterone bilaterally in the central amygdala, followed by infusion of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) during the fourth week after surgery. Corticosterone-induced mechanical allodynia was completely reversed by SAHA administration, while visceral hyperalgesia was partially ameliorated. Ligon and colleagues suggest that epigenetic modifications induced by HDACs contribute to persistent IBS symptoms, and that maintenance of histone acetylation could be beneficial in treating the disorder.
An mGluR3 mechanism
Ligon’s neighbor at the poster session, Richard Traub, University of Maryland, Baltimore, US, also presented findings suggesting that HDAC inhibition prevents stress-induced visceral hypersensitivity in rats. In this model, three days of the stressful forced swim paradigm results in elevated levels of visceral pain, as measured by the visceromotor response induced by colorectal distention.
Compared to the vehicle-treated condition, pretreatment with SAHA resulted in less visceral pain along with increased acetylation levels of lysine 9 on histone 3 (H3K9) in the dorsal spinal cord. It also reduced two stress-induced behaviors—time spent immobilized and number of fecal pellets produced—during the forced swim. The researchers observed a similar effect on visceral hypersensitivity when they administered SAHA after the forced swim test.
Treatment with a metabotropic glutamate receptor 2/3 (mGluR2/3) antagonist following the post-swimming SAHA treatment reversed the reduction in visceral pain observed from SAHA alone. Traub and colleagues then showed that SAHA pretreatment elevated the mRNA and protein levels of mGluR3, but not mGluR2, in the dorsal spinal cord by increasing the binding of acetylated H3K9 to the promoter of Grm3, the gene encoding mGluR3. Consistent with Ligon’s results, the data suggest that increasing histone acetylation and the activity of mGluR3 may be a novel treatment strategy for IBS and other stress-induced visceral pain.
Modality-specific effects
Despite troubling side effects, tricyclic antidepressants (TCAs) can provide partial relief from both chronic pain and depression, which often go hand in hand. Based on evidence implicating one particular histone deacetylase, HDAC5, in both depression and TCA’s mechanism of action (Tsankova et al., 2006), Giannina Descalzi at Mt. Sinai, New York City, US, examined HDAC5’s role in neuropathic and inflammatory pain. The findings were presented in a poster session held on Wednesday morning, November 19.
Inflammatory pain was modeled by an inter-plantar injection of complete Freund’s adjuvant. In comparison to wild-type animals, mice lacking HDAC5 showed less mechanical allodynia. They also displayed increased levels of anxiety, as measured by the novelty suppressed feeding test.
Descalzi and colleagues modeled neuropathic pain using spared nerve injury and sciatic nerve severing. In contrast to inflammatory pain, deletion of HDAC5 did not affect the development of mechanical hypersensitivity after nerve injury. Much to the researchers’ surprise, HDAC5 knockouts did show a more pronounced improvement in neuropathic pain following treatment with the TCA desipramine than wild-types, which the researchers suggest is due to an earlier onset of the drug’s action in the knockouts. Consistent with these results, overexpression of HDAC5 resulted in a reduction of desipramine’s efficacy.
Western blotting studies showed that SNI resulted in decreased levels of phosphorylated HDAC5 in the nucleus accumbens, while desipramine treatment in sham-treated animals had the opposite effect. Using subcellular fractionation and co-immunoprecipitation, the researchers found that, in SNI animals treated with desipramine, HDAC5 assembles in a complex with G protein subunits and is transported to the nucleus where it silences gene expression. HDAC5 inhibition could be used to potentiate TCA-induced pain relief in neuropathic pain, the researchers conclude, resulting in smaller doses (and fewer side effects) from the antidepressant.
Allison Marin (Curley), PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.
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