Histone Deacetylase Inhibitors Counteract CGRP Signaling and Pronociceptive Sensitization in a Rat Model of Medication Overuse Headache

  • Author Footnotes
    # These authors contributed equally to this work.
    Matteo Urru
    # These authors contributed equally to this work.
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Author Footnotes
    # These authors contributed equally to this work.
    Daniela Buonvicino
    Address reprint requests to Daniela Buonvicino, PhD. Department of Health Sciences. Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
    # These authors contributed equally to this work.
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Alessandra Pistolesi
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Sara Paccosi
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Alberto Chiarugi
    Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
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  • Author Footnotes
    # These authors contributed equally to this work.


      • Chronic exposure of rat to eletriptan induces CGRP and its receptor expression in TG but not in TNc.
      • HDAC inhibitors, Panobinostat and givinostat prevent overexpression of CGRP and its receptor in TG.
      • Both inhibitors counteract photophobic behavior and cephalic allodynia in eletriptan-exposed rats.
      • Both drugs prevent hypersensitivity to capsaicin-induced vasodilatation in eletriptan-exposed rats.
      • Data support the therapeutic potential of HDAC inhibition in preventing migraine chronification.


      Chronic triptan exposure in rodents recapitulates medication overuse headache (MOH), causing cephalic pain sensitization and trigeminal ganglion overexpression of pronociceptive proteins including CGRP. Because of these transcriptional derangements, as well as the emerging role of epigenetics in chronic pain, in the present study, we evaluated the effects of the histone deacetylase inhibitors (HDACis) panobinostat and givinostat, in rats chronically exposed to eletriptan for 1 month. Both panobinostat and givinostat counteracted overexpression of genes coding for CGRP and its receptor subunit RAMP1, having no effects on CLR and RCP receptor subunits in the trigeminal ganglion (TG) of eletriptan-exposed rats. Within the trigeminal nucleus caudalis (TNc), transcripts for these genes were neither upregulated by eletriptan nor altered by concomitant treatment with panobinostat or givinostat. HDACis counteracted hypersensitivity to capsaicin-induced vasodilatation in the trigeminal territory, as well as photophobic behavior and cephalic allodyniain eletriptan-exposed rats. Eletriptan did not affect CGRP, CLR, and RAMP1 expression in cultured trigeminal ganglia, whereas both inhibitors reduced transcripts for CLR and RAMP-1. The drugs, however, increased luciferase expression driven by CGRP promoter in cultured cells. Our findings provide evidence for a key role of HDACs and epigenetics in MOH pathogenesis, highlighting the therapeutic potential of HDAC inhibition in the prevention of migraine chronification.


      The present study highlights a key epigenetic role of HDAC in the rodent model of medication overuse headache, furthering our understanding of the molecular mechanisms responsible for pronociceptive sensitization during headache chronification.

      Key words


      ANOVA (Analysis of Variance), CGRP (Calcitonin Gene-Related Peptide), CLR (Calcitonin-like receptor), CNS (Central nervous system), DIV (days in vitro, HDAC, Histone deacetylase), HDACi (Histone deacetylase inhibitor), MOH (Medication overuse headache), PCR (Polymerase Chain Reaction), RAMP1 (Receptor Activity Modifying Protein 1), RCP (receptor component protein), SEM (Standard error of the mean), TG (trigeminal ganglion), TNc (trigeminal nucleus caudalis)
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