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Updated: May 4, 2026
Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies
Published on: October 6, 2022
Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of
1Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Avenue - E-31, Cleveland, OH 44195, USA.
Aims:
Patients receiving paclitaxel often develop peripheral neuropathies. We found that a novel selective cannabinoid CB2 receptor agonist (MDA7) prevents paclitaxel-induced mechanical allodynia in rats and mice. Here we investigated gene expression profiling in the lumbar spinal cord after 14-day treatment of MDA7 in paclitaxel animals and analyzed possible signaling pathways underlying the preventive effect of MDA7 on paclitaxel-induced neuropathy.
Methods:
Peripheral mechanical allodynia was induced in rats or mice receiving intraperitoneal (i.p.) injection of paclitaxel at a dose of 1mg/kg daily for four consecutive days. MDA7 was administered at a dose of 15mg/kg 15min before paclitaxel and then continued daily for another 10days. Whole-genome gene expression profiling in the lumbar spinal cord of MDA7 and paclitaxel-treated rats was investigated using microarray analysis. The Ingenuity pathway analysis was performed to determine the potential relevant canonical pathways responsible for the effect of MDA7 on paclitaxel-induced peripheral neuropathy.
Results:
We observed that the inflammatory molecular networks including tumor necrosis factor (TNF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), transforming growth factor beta (TGFβ), and mitogen-activated protein kinases (MAPK) signaling are most relevant to the preventive effect of MDA7 on paclitaxel-induced peripheral neuropathy. In addition, genes encoding molecules that are important in central sensitization such as glutamate transporters and N-methyl-d-aspartate receptor 2B (NMDAR2B), and neuro-immune-related genes such as neuronal nitric oxide synthase (nNOS1), chemokine CX3CL1 (a mediator for microglial activation), toll-like receptor 2 (TLR2), and leptin were differentially modulated by MDA7.
Conclusion:
The preventive effect of MDA7 on paclitaxel-induced peripheral allodynia in rats may be associated with genes involved in signal pathways in central sensitization, microglial activation, and neuroinflammation in the spinal cord.
Insights
A novel cannabinoid CB2 receptor agonist, MDA7, prevents paclitaxel-induced nerve pain by modulating spinal cord gene expression. This suggests potential therapeutic pathways for chemotherapy-induced peripheral neuropathy.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Paclitaxel chemotherapy can cause debilitating peripheral neuropathies.
- Mechanical allodynia is a common symptom of paclitaxel-induced neuropathy.
Purpose of the Study:
- To investigate the gene expression profile in the spinal cord of animals treated with MDA7 and paclitaxel.
- To identify signaling pathways involved in MDA7's preventive effect on paclitaxel-induced neuropathy.
Main Methods:
- Paclitaxel-induced mechanical allodynia was established in rats and mice.
- MDA7 was administered to paclitaxel-treated animals.
- Whole-genome gene expression profiling was performed using microarray analysis on lumbar spinal cord tissue.
- Ingenuity pathway analysis was used to identify relevant canonical pathways.
Main Results:
- Inflammatory networks including TNF, NF-κB, TGFβ, and MAPK signaling were most relevant.
- MDA7 modulated genes involved in central sensitization (glutamate transporters, NMDAR2B).
- Neuro-immune-related genes (nNOS1, CX3CL1, TLR2, leptin) were also differentially modulated.
Conclusions:
- MDA7's preventive effect on paclitaxel-induced allodynia is linked to modulation of central sensitization pathways.
- Microglial activation and neuroinflammation pathways in the spinal cord are implicated.
- These findings suggest MDA7's potential as a therapeutic agent for chemotherapy-induced peripheral neuropathy.
