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

Abstract

ABSTRACT: Neuropathic pain (NP) is a debilitating chronic syndrome that is often refractory to currently available analgesics. The maintenance of NP encompasses 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 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 and 3B were significantly up-regulated in the spinal dorsal horn and dorsal root ganglia 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. 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.Esta tesis ha sido financiada con ayudas a la investigación procedentes de: - Beca predoctoral de Neurociencia: Fundación Tatiana Pérez de Guzmán el Bueno. - Instituto de investigación sanitaria Marqués de Valdecilla - Ministerio de Economía y Competitividad a través de los Proyectos del Plan Estatal: SAF2013-47434-R y SAF2016-77732-