Upregulated spinal histone deacetylases induce nociceptive sensitization by inhibiting the GABA system in chronic constriction injury–induced neuropathy in rats

PAIN Reports, 2024 · DOI: http://dx.doi.org/10.1097/PR9.0000000000001209 · Published: November 6, 2024

Simple Explanation

Neuropathic pain is a chronic condition with limited effective treatments. This study investigates the role of histone deacetylases (HDACs) in neuropathic pain, focusing on their impact on GABA, a neurotransmitter that inhibits pain. The research found that specific HDACs (HDAC3, HDAC4, and HDAC6) were elevated in rats with nerve injury, while GABA levels decreased. This suggests HDACs may contribute to pain by reducing GABA's inhibitory effects. Administering an HDAC inhibitor reduced pain and restored GABA levels in the rats, indicating that targeting HDACs could be a potential strategy for managing neuropathic pain.

Study Duration

28 days

Participants

Adult male Wistar rats (250 to 285 g)

Evidence Level

Not specified

Key Findings

1
Spinal hdac3, hdac4, and hdac6 were upregulated in CCI rats, indicating their potential role in neuropathic pain.
2
HDAC3, HDAC4, and HDAC6 protein levels were significantly upregulated, whereas GABA and GAD65 were dramatically downregulated in CCI rats.
3
Intrathecal administration of panobinostat attenuated nociceptive behavior and restored GAD65 and GABA expression in CCI rats, suggesting its therapeutic potential.

Research Summary

This study investigates the role of spinal HDACs in chronic constriction injury (CCI)-induced neuropathic pain in rats, focusing on the GABA system. The results demonstrate that CCI upregulates HDAC3, HDAC4, and HDAC6 expression in the spinal cord, while downregulating GABA and its synthesis enzyme GAD65. Treatment with the HDAC inhibitor panobinostat attenuated pain behavior and restored GABA and GAD65 expression, suggesting HDACs as a potential therapeutic target for neuropathic pain.

Practical Implications

Therapeutic Target Identification

HDAC3, HDAC4, and HDAC6 are identified as potential therapeutic targets for managing neuropathic pain.

Drug Repurposing

Panobinostat, an FDA-approved HDAC inhibitor, shows promise in alleviating neuropathic pain symptoms.

Epigenetic Approach to Pain Management

Modulating histone acetylation through HDAC inhibition represents a novel epigenetic strategy for neuropathic pain treatment.

Study Limitations

1
The study was conducted on rats, and the results may not directly translate to humans.
2
The precise mechanisms of HDAC3/4 cytoplasmic/nuclear ratio in SCDH neurons remain unclear.
3
The study did not examine the cytoplasmic/nuclear ratio of HDAC3/4.

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