Diversity of microglial transcriptional responses during opioid exposure and neuropathic pain
Elizabeth I Sypek1,2,3,4, Adrien Tassou5, Hannah Y Collins6
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, United States.
Abstract:
Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Microglia display similar morphological responses in the spinal cord after peripheral nerve injury (PNI). Consistent with this observation, functional studies have suggested that microglia activated by opioids or PNI engage common molecular mechanisms to induce hypersensitivity. In this article, we conducted deep RNA sequencing (RNA-seq) and morphological analysis of spinal cord microglia in male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple models of OIH and PNI. After PNI, we identify an early proliferative transcriptional event across models that precedes the upregulation of histological markers of microglial activation. However, we found no proliferative transcriptional response associated with opioid-induced microglial activation, consistent with histological data, indicating that the number of microglia remains stable during morphine treatment, whereas their morphological response differs from PNI models. Collectively, these results establish the diversity of pain-associated microglial transcriptomic responses and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other central nervous system pathologies.
Insights
Microglia in the spinal cord change shape with opioid treatment and nerve injury. However, RNA sequencing reveals distinct molecular responses, suggesting targeted treatments for pain conditions.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia, the immune cells of the central nervous system, alter their morphology in response to chronic opioid treatment and peripheral nerve injury (PNI).
- This microglial activation is linked to opioid-induced hyperalgesia (OIH) and pain hypersensitivity following PNI.
- Common molecular mechanisms have been proposed for opioid- and PNI-induced microglial activation.
Purpose of the Study:
- To comprehensively analyze the transcriptional states and identify common molecular mechanisms between OIH and PNI models.
- To compare the microglial responses to opioid treatment versus PNI using deep RNA sequencing and morphological analysis.
Main Methods:
- Deep RNA sequencing (RNA-seq) of spinal cord microglia from male mice.
- Morphological analysis of microglia.
- Comparison of transcriptional profiles between opioid-induced hyperalgesia and peripheral nerve injury models.
Main Results:
- Peripheral nerve injury (PNI) induced an early, proliferative transcriptional response in microglia preceding histological activation markers.
- Opioid treatment did not elicit a proliferative transcriptional response in microglia; their numbers remained stable.
- Morphological changes in microglia differed between opioid treatment and PNI models, despite functional similarities in inducing hypersensitivity.
Conclusions:
- Microglial transcriptomic responses to pain stimuli are diverse and insult-specific.
- Targeting distinct, injury-specific microglial pathways may be crucial for effectively treating OIH, PNI, and other central nervous system disorders.
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