Diversity of microglial transcriptional responses during opioid exposure and neuropathic pain
Abstract/Contents
- Abstract
- Opioids, such as morphine, remain some of the most widely prescribed medications in the world for the treatment of pain despite their detrimental side effects. In particular, analgesic tolerance and opioid-induced hyperalgesia (OIH) can lead to dose escalation and increased risk of addiction and overdose death. As we are experiencing an Opioid Epidemic with high rates of mortality, there is a strong need to both understand and miti-gate these detrimental opioid effects or to identify alternative non-opioid analgesics. Mi-croglia, the resident tissue macrophages of the central nervous system, take on altered morphology in response to chronic opioid treatment, similarly to their response to pe-ripheral nerve injury (PNI). Functional studies have suggested that microglial activation by PNI or opioids engage common mechanisms to alter spinal neural excitability, con-tributing to chronic neuropathic pain after PNI or to opioid tolerance and OIH, which counteract morphine analgesia. We thus sought to determine if there was a common pro-nociceptive state of microglia that could be a potential target for novel pain therapeutics. To this aim, we conducted RNA sequencing (RNA-seq) of acutely isolated spinal cord microglia, first to comprehensively interrogate transcriptional state commonality between multiple PNI pain models over time. We identified a common early proliferative event, corresponding to the greatest transcriptional variance, and preceding the peak of histo-logical markers of microglia activation. This initial transcriptional profile was followed by a weak transcriptional signature of immune activation that varied between models. We next probed the effects of chronic morphine with the same RNA-seq approach. Strikingly, contrary to the prevailing view in the pain and opioid fields, we found that microglia did not express the classic receptor for morphine, the mu opioid receptor, nor was this receptor required for opioid-induced microglia activation. In support of an ab-sence of a singular and common pronociceptive microglial response, we demonstrate that the transcriptional responses following PNI did not occur with morphine treatment. Meta-analysis further revealed dynamic transcriptional signatures of microglial reactivity that diverge between PNI, OIH, and CNS pathology, despite similar histological out-comes. Collectively, our results provide a resource of pain-associated microglial tran-scriptomes that expand our understanding of microglial responses to insults and caution against extrapolation of microglial activation status based on morphological analysis.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Sypek, Elizabeth Irene |
|---|---|
| Degree supervisor | Scherrer, Gregory |
| Thesis advisor | Scherrer, Gregory |
| Thesis advisor | Buckwalter, Marion |
| Thesis advisor | Goodman, Miriam Beth |
| Thesis advisor | Plant, Giles |
| Degree committee member | Buckwalter, Marion |
| Degree committee member | Goodman, Miriam Beth |
| Degree committee member | Plant, Giles |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Elizabeth Irene Sypek. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Elizabeth Sypek
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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