Neuropathic pain induced by nerve injury involves epigenetic changes and chromatolytic damage in the somatosensory nervous system: effects of miR-30c-5p gain and loss of function

• Autores: Raquel Francés Romero
• Directores de la Tesis: María Amor Hurlé González (dir. tes.), Mónica Tramullas Fernández (codir. tes.)
• Lectura: En la Universidad de Cantabria ( España ) en 2019
• Idioma: inglés
• Tribunal Calificador de la Tesis: Fernando Cervero (presid.), Carmen Martínez-Cué Pesini (secret.), Maria Clemencia Hernandez (voc.)
• Programa de doctorado: Programa de Doctorado en Biología Molecular y Biomedicina por la Universidad de Cantabria
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: UCrea
• Resumen

  • Neuropathic pain (NP) is a debilitating chronic syndrome that is often refractory to currently available analgesics. The development and maintenance of NP encompass long term pathological plasticity in the nervous system that may be explained by alterations in the epigenetic mechanisms and cellular processes that underlie this disease. In addition, aberrant expression of several microRNAs (miRNAs) in nociception-related neural structures is associated with NP in rodent models. Previous results from our group show that, after sciatic nerve injury in rats, miR-30c-5p is up-regulated in the spinal cord (SDH) and dorsal root ganglia (DRG), and that the expression of miR-30c-5p positively correlated with the severity of allodynia. The administration of a miR-30c-5p inhibitor into the cisterna magna of the brain delayed neuropathic pain development and reversed fully established allodynia in rodents.

    In this thesis, we investigated the involvement of epigenetic mechanisms in neuropathic pain establishment and chronification and the effects of modulating miR-30c-5p in the somatosensory nervous system. The transcript levels of DNA methyltransferase-3A (DNMT3A) and 3B (DNMT3b) were significantly up-regulated in the SDH and DRG from neuropathic rats. This upregulation was potentiated when neuropathic rats were treated with a miR-30c-5p inhibitor. In parallel, both structures exhibited increased methylation at cytosine in CpG islands, assessed by immunofluorescence with Ab to 5-methylcytosine, as well as trimethylation of histone H3K9, assessed by Ab to H3K9me3. By luciferase assay, we demonstrated a post-transcriptional regulation for DNMT3B and DNMT3A by miR-30c-5p.

    Furthermore, we demonstrated that NP induces an increase in the chromatolytic damage suffered by DRG neurons. This phenomenon was potentiated when neuropathic rats were treated with a miR-30c-5p mimic. We showed that miR-30c-5p treatment induces reorganization and loss of nucleolar transcription units, segregation of dense fibrillar and granular components and a depletion of cajal bodies.

    We propose that miR-30c-5p modulation in NP plays an essential role in the epigenetic mechanism and cellular processes that underlie this disease.