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Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
RNA-binding protein MBNL2 mitigates neuropathic pain after chemotherapy through destabilizing CCR2 expression in
Keshi Yan1, Ruining Ma1, Bing Wang1
1Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
Abstract:
Chemotherapy drug-induced changes of gene expression in the dorsal root ganglion (DRG) are critical for the genesis of chemotherapy-induced neuropathic pain (CINP). However, the mechanisms driving these changes remain elusive. Here, we report the downregulation of muscleblind-like protein 2 (MBNL2), an RNA-binding protein, in the DRG neurons after intraperitoneal injection of paclitaxel. Rescuing this downregulation blocks an increase of the C-C chemokine receptor type 2 (CCR2) in the DRG and mitigates paclitaxel-induced mechanical allodynia, heat and cold hyperalgesia and ongoing pain. Conversely, DRG downregulation of MBNL2 increases the expression of CCR2 in the DRG neurons and leads to CINP-like symptoms in naïve mice. Mechanistically, paclitaxel-induced downregulation of MBNL2 reduces its binding to the 3'-untranslated region of Ccr2 mRNA, thereby enhancing the stability of Ccr2 mRNA in the DRG. Given that MBNL2 and CCR2 are co-expressed in DRG neurons, these findings suggest that MBNL2 alleviates CINP, likely by destabilizing CCR2 expression in the DRG, and may represent a promising therapeutic strategy for this condition.
Insights
Muscleblind-like protein 2 (MBNL2) downregulation in dorsal root ganglion (DRG) neurons causes chemotherapy-induced neuropathic pain (CINP) by increasing C-C chemokine receptor type 2 (CCR2). Restoring MBNL2 alleviates CINP symptoms.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy-induced neuropathic pain (CINP) arises from gene expression changes in dorsal root ganglion (DRG) neurons.
- The precise molecular mechanisms underlying these gene expression alterations in CINP remain largely unknown.
Purpose of the Study:
- To investigate the role of muscleblind-like protein 2 (MBNL2) in the development of paclitaxel-induced neuropathic pain.
- To elucidate the molecular mechanisms by which MBNL2 influences gene expression in DRG neurons relevant to CINP.
Main Methods:
- Paclitaxel injection in mice to induce neuropathic pain.
- Analysis of MBNL2 and C-C chemokine receptor type 2 (CCR2) expression in DRG neurons.
- Experimental manipulation of MBNL2 levels in DRG neurons.
- Assessment of pain behaviors including mechanical allodynia and thermal hyperalgesia.
Main Results:
- Paclitaxel treatment downregulated MBNL2 expression in DRG neurons.
- MBNL2 downregulation led to increased CCR2 expression and CINP-like symptoms.
- Restoring MBNL2 expression in DRG neurons mitigated paclitaxel-induced pain behaviors.
- MBNL2 directly binds to Ccr2 mRNA, regulating its stability and subsequent CCR2 protein levels.
Conclusions:
- MBNL2 plays a critical neuroprotective role in alleviating chemotherapy-induced neuropathic pain.
- The MBNL2-CCR2 axis in DRG neurons represents a potential therapeutic target for managing CINP.
- Understanding MBNL2's function offers insights into novel strategies for pain management.
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