Epigenetic mechanisms of chronic pain that prime susceptibility to future opioid exposure
Description
TitleEpigenetic mechanisms of chronic pain that prime susceptibility to future opioid exposure
Date Created2022
Other Date2022-05 (degree)
Extent44 pages : illustrations
DescriptionNeuropathic pain is defined by The International Association for the Study of Pain (IASP) as pain caused by a lesion or disease of the central or peripheral somatosensory system. Neuropathic pain is a chronic condition that is associated with numerous comorbidities. Different treatment strategies for neuropathic pain are available dependent on the type of nerve damage, location, and potential cause (National Institute of Neurological Disorders and Stroke). Opioids are a class of drugs that are commonly prescribed to individuals suffering from both acute and chronic pain. Prolonged opioid intake may result in dependence and addiction. The National Institute on Drug Abuse reported 128 people were dying daily in the United States due to opioid overdoses in 2018. Thus, the need for a new safe treatment strategy of chronic pain has emerged, and it requires a better understanding of the mechanisms underlying pain. Studies of epigenetic changes that are involved in chronic pain induction and maintenance can lead to a development of novel therapeutics. In the proposed experiments we used the spared nerve injury in mice as a peripheral neuropathic pain model, this model previously has shown robust and prolonged behavioral modifications in operated subjects (Decosterd and Woolf, 2000). We assessed the following epigenetic modifications: tri-methylation on lysine 4 of histone H3 (H3K4me3) and acetylation of lysine 27 of histone H3 (H3K27Ac), both of which are associated with active transcription, monomethylated H3K4 (H3K4me1), a marker of open chromatin associated with both active transcription or a permissive state that promotes future gene expression and histone methyltransferase SET Domain Containing 7, SETD7, that specifically monomethylates Lys-4 of histone H3. We considered the following key supraspinal structures engaged in pain modulation: periaqueductal gray (PAG) (Mokhtar & Singh, 2021) and the lateral hypothalamus (LH) (Fakhoury et al., 2020). Additionally, we have examined the described epigenetic markers in two structures of the mesolimbic pathway, the ventral tegmental area (VTA) and the nucleus accumbens (NAc), taking into consideration the growing evidence suggesting an important role of the mesolimbic pathway in chronic pain (Watanabe et al., 2018; Markovic et al., 2021). Moreover, we investigated potential involvement of SETD7 expression in the VTA on oral fentanyl consumption in mice subjected to chronic pain. Furthermore, we evaluated levels of pro-inflammatory cytokine Interleukin-1β (IL-1β), upregulation of which was demonstrated in pathogenesis of chronic pain (Gui et al., 2016; Mailhot et al., 2020) and reported to be associated with the increase of SETD7 and H3K4me1 (Shen et al., 2019).
NoteM.S.
NoteIncludes bibliographical references
Genretheses
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
Statistical Profile