Long-range action of an HDAC inhibitor treats chronic pain in a spared nerve injury rat model

bioRxiv preprint, 2023 · DOI: https://doi.org/10.1101/2023.12.13.571583 · Published: December 14, 2023

Simple Explanation

This research investigates a novel approach to treating chronic pain using a triple combination formulation (TCF) containing an HDAC inhibitor called vorinostat. The TCF aims to improve the efficacy and duration of pain relief while minimizing side effects and reducing the total dosage of the HDAC inhibitor. The study uses a spared nerve injury (SNI) model in rats and mice to assess the TCF's effectiveness in reducing neuropathic pain.

Study Duration

65 Weeks

Participants

Sprague-Dawley rats (both aged male and young, 200-250g) and adult male C57BL/6 mice (25-31g)

Evidence Level

Not specified

Key Findings

1
A single injection of the TCF significantly reduced mechanical allodynia (pain from normally non-painful stimuli) for up to four weeks in SNI rats.
2
Doubling the dose of vorinostat in the TCF resulted in a greater amplitude and longer duration of pain relief, lasting for over two months, but this effect was specific to male rats.
3
The TCF reduced inflammatory markers and microglia activation in the spinal cord, suggesting a mechanism of action involving the reduction of inflammation.

Research Summary

The study demonstrates that a triple combination formulation (TCF) containing the HDAC inhibitor vorinostat can effectively treat chronic neuropathic pain in a spared nerve injury (SNI) rat model. A single injection of TCF provided long-lasting pain relief, reduced spinal cord inflammation, and did not cause significant side effects. Increasing the dose of vorinostat in the TCF further enhanced its efficacy and duration of action, particularly in male rats, suggesting a potential for personalized pain management strategies.

Practical Implications

Novel Non-Opioid Treatment

The TCF presents a promising non-opioid treatment option for chronic pain, addressing the urgent need for alternatives to opioid-based medications.

Reduced Dosage and Side Effects

The TCF enables single-dose effectiveness with extended action, reducing the overall dosage of HDAC inhibitors and potentially minimizing long-term side effects.

Personalized Pain Management

The gender-specific response to increased vorinostat dosage in the TCF suggests the potential for personalized pain management strategies based on individual patient characteristics.

Study Limitations

1
The study primarily focused on tactile sensitivity, with limited assessment of other pain modalities such as heat hyperalgesia.
2
The long-lasting effects of TCF made it challenging to assess the affective component of neuropathic pain.
3
The gender-specific response to the TCF warrants further investigation to understand the underlying mechanisms and optimize treatment strategies for both males and females.

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