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Browsing by Author "El Jordi, Omar"
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Item Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice(Frontiers Media, 2022-12-16) El Jordi, Omar; Fischer, Kathryn D.; Meyer, Timothy B.; Atwood, Brady K.; Oblak, Adrian L.; Pan, Raymond W.; McKinzie, David L.; Pharmacology and Toxicology, School of MedicineOpioid Use Disorder (OUD) affects approximately 8%–12% of the population. In dependent individuals, abrupt cessation of opioid taking results in adverse withdrawal symptoms that reinforce drug taking behavior. Considerable unmet clinical need exists for new pharmacotherapies to treat opioid withdrawal as well as improve long-term abstinence. The neuroimmune system has received much scientific attention in recent years as a potential therapeutic target to combat various neurodegenerative and psychiatric disorders including addiction. However, the specific contribution of microglia has not been investigated in oxycodone dependence. Chronic daily treatment with the CSF1R inhibitor Pexidartinib (PLX3397) was administered to knockdown microglia expression and evaluate consequences on analgesia and on naloxone induced withdrawal from oxycodone. In vivo results indicated that an approximately 40% reduction in brain IBA1 staining was achieved in the PLX treatment group, which was associated with a delay in the development of analgesic tolerance to oxycodone and maintained antinociceptive efficacy. Acute withdrawal behavioral symptoms, brain astrocyte expression, and levels of many neuroinflammatory markers were not affected by PLX treatment. KC/GRO (also known as CXCL1) was significantly enhanced in the somatosensory cortex in oxycodone‐treated mice receiving PLX. Microglial knock-down did not affect the expression of naloxoneinduced opioid withdrawal but affected antinociceptive responsivity. The consequences of increased KC/GRO expression within the somatosensory cortex due to microglial reduction during opioid dependence are unclear but may be important for neural pathways mediating opioid‐induced analgesia.Item The Role of Inflammation in Mediating Different Cognitive and Behavioral Functions(2023-03) El Jordi, Omar; Atwood, Brady K.; McKinzie, David L.; Oblak, Adrian L.; Block, Michelle L.; Sheets, Patrick L.Inflammation, specifically brain inflammation, can be both neuroprotective as well as detrimental in multiple neuropathic diseases. We investigated the inflammatory profile in two different receptor systems, opioids, and estrogens. Microglia, brain immune cells, can influence the neuron’s microenvironment and regulate neuronal activity via multiple signaling mediators. We investigated the role of microglia in opioid withdrawal in an oxycodone dependence paradigm. We found that microglial reduction had no effect on opioid withdrawal symptoms, glial activation markers, body temperature dysregulation, or select inflammatory cytokines. Interestingly, we found them involved in the acquisition of analgesic tolerance potentially mediated by the chemokine KC/GRO. This suggests that microglia modulate neuron adaptations to repetitive opioid dosing through chemokines or alternatively through direct interaction (cell-to-cell), indirect interaction through cytokines, or neurotransmitters that were not measured. In a different experiment, we investigated the effect of Raloxifene, a selective estrogen receptor modulator, in a model of lower back pain/spinal damage precipitated by intervertebral disc degeneration. Raloxifene’s therapeutic effect at the molecular level, verified by collaborators and evident by regeneration of healthy intervertebral disc tissue and reduction of pain signaling molecules (Substance P), did not translate to behavior. Our behavioral measures evaluating motor and psychological deficit, and ataxia were not altered by treatment. Interestingly, we found that hedonic behavior improved by the end of the treatment suggesting that Raloxifene may have a therapeutic effect on adverse sensory signals such as back pain resulting in reward-seeking behavior.