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The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
DNMT3a methylation in neuropathic pain
Cuijie Shao1, Yong Gao1, Dan Jin1
1Department of Pain, Binzhou Medical University Hospital, Binzhou, China.
Background:
Mu opioid receptor (MOR) plays a crucial role in mediating analgesic effects of opioids and is closely associated with the pathologies of neuropathic pain. Previous studies have reported that peripheral nerve injury downregulates MOR expression, but the epigenetic mechanisms remain unknown.
Objective:
Therefore, we investigated DNA methyltransferase3a (DNMT3a) expression or methylation changes within MOR promoter in the spinal cord in a neuropathic pain induced by a chronic constriction injury (CCI) mouse model and further determined whether these injury-associated changes are reversible by pharmacological interventions.
Methods:
A CCI mouse model was established and tissue specimens of lumbar spinal cords were collected. The nociception threshold was evaluated by a Model Heated 400 Base. DNMT3a and MOR mRNA and protein level were detected by real-time-polymerase chain reaction and Western blot, respectively. Methylation of DNMT3a gene was measured by methylation-specific PCR.
Results:
Our data showed that chronic nerve injury led to a significant upregulation of DNMT3a expression that was associated with increased methylation of MOR gene promoter and decreased MOR protein expression in the spinal cord. Inhibition of DNMT3a catalytic activity with DNMT inhibitor RG108 significantly blocked the increase in methylation of the MOR promoter, and then upregulated MOR expression and attenuated thermal hyperalgesia in neuropathic pain mice.
Conclusion:
This study demonstrates that an increase of DNMT3a expression and MOR methylation epigenetically play an important role in neuropathic pain. Targeting DNMT3a to the promoter of MOR gene by DNMT inhibitor may be a promising approach to the development of new neuropathic pain therapy.
Insights
Neuropathic pain involves changes in mu opioid receptor (MOR) expression. This study shows DNA methyltransferase3a (DNMT3a) increases MOR promoter methylation, reducing MOR expression and worsening pain. Inhibiting DNMT3a offers a potential therapy.
Area of Science:
- Neuroscience
- Epigenetics
- Pain Research
Background:
- Mu opioid receptor (MOR) is vital for opioid analgesia and neuropathic pain.
- Peripheral nerve injury reduces MOR expression, but epigenetic mechanisms are unclear.
Purpose of the Study:
- Investigate DNA methyltransferase3a (DNMT3a) changes in the MOR promoter in a mouse model of neuropathic pain.
- Determine if pharmacological interventions can reverse these injury-associated changes.
Main Methods:
- Established a chronic constriction injury (CCI) mouse model.
- Assessed nociception thresholds, DNMT3a and MOR mRNA/protein levels, and MOR promoter methylation via PCR and Western blot.
Main Results:
- CCI mice showed increased DNMT3a expression, higher MOR promoter methylation, and decreased MOR protein.
- DNMT inhibitor RG108 blocked MOR promoter methylation, increased MOR expression, and reduced thermal hyperalgesia.
Conclusions:
- Increased DNMT3a and MOR methylation play a key epigenetic role in neuropathic pain.
- Targeting DNMT3a with inhibitors may offer a novel therapeutic strategy for neuropathic pain.
