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Updated: Jul 15, 2025
Author Spotlight: Utilizing Infraorbital Nerve Ligation in Mice for Investigating Trigeminal Neuropathic Pain and Treatment Strategies
Published on: March 8, 2024
Epigenetic HDAC5 Inhibitor Reverses Craniofacial Neuropathic Pain in Mice
Karin N Westlund1, Marena Montera1, Aleyah E Goins1
1Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
Abstract:
Identifying and resolving molecular complexities underlying chronic neuropathic pain is a significant challenge. Among the numerous classes of histone deacetylases, Class I (HDAC 1-3) and Class III (sirtuins) have been best studied in experimental pain models where inhibitor pre-treatments but not post-treatments abrogate the development of pain-related behaviors. Post-treatment here in week 3 with less well-studied Class IIa HDAC4/5 selective inhibitor LMK235 diminishes the trigeminal ganglia increases of HDAC5 RNA and protein in two chronic orofacial neuropathic pain models to levels measured in naïve mice at week 10 post-model induction. HDAC4 RNA reported in lower limb inflammatory pain models is not evident in the trigeminal models. Many other gene alterations persisting at week 10 in the trigeminal ganglia (TG) are restored to naïve levels in mice treated with LMK235. Important pain-related upregulated genes Hoxc8,b9,d8; P2rx4, Cckbr, growth hormone (Gh), and schlafen (Slfn4) are greatly reduced in LMK235-treated mice. Fold increase in axon regeneration/repair genes Sostdc1, TTr, and Folr1 after injury are doubled by LMK235 treatment. LMK235 reduces the excitability of trigeminal ganglia neurons in culture isolated from nerve injured mice compared to vehicle-treated controls, with no effect on neurons from naïve mice. Electrophysiological characterization profile includes a shift where ∼20% of the small neurons recorded under LMK235-treated conditions are high threshold, whereas none of the neurons under control conditions have high thresholds. LMK235 reverses long-standing mechanical and cold hypersensitivity in chronic trigeminal neuropathic pain models in males and females (5,10 mg/kg), preventing development of anxiety- and depression-like behaviors. PERSPECTIVE: Data here support HDAC5 as key epigenetic factor in chronic trigeminal neuropathic pain persistence, validated with the study of RNA alterations, TG neuronal excitability, and pain-related behaviors. HDAC5 inhibitor given in week 3 restores RNA balance at 10 weeks, while upregulation remains for response to wound healing and chronic inflammation RNAs.
Insights
A selective HDAC5 inhibitor, LMK235, reverses chronic neuropathic pain and associated behaviors by restoring gene expression and neuronal excitability in trigeminal ganglia. This epigenetic therapy offers a new approach for pain management.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Chronic neuropathic pain presents significant molecular challenges.
- Class I and III histone deacetylases (HDACs) are studied in pain models, but Class IIa HDACs are less understood.
- Previous studies show HDAC inhibitors are effective pre-treatments, but post-treatment efficacy is less clear.
Purpose of the Study:
- To investigate the role of Class IIa HDACs, specifically HDAC5, in chronic trigeminal neuropathic pain.
- To evaluate the efficacy of a selective HDAC4/5 inhibitor, LMK235, as a post-treatment for established neuropathic pain.
- To explore the molecular and electrophysiological effects of LMK235 on trigeminal ganglia (TG) neurons.
Main Methods:
- Administered LMK235 post-induction in chronic orofacial neuropathic pain models.
- Analyzed HDAC5 RNA and protein levels, gene expression profiles, and neuronal excitability in TG.
- Assessed behavioral outcomes including mechanical/cold hypersensitivity and anxiety/depression-like behaviors.
Main Results:
- LMK235 post-treatment reduced HDAC5 expression and restored numerous gene alterations in TG to naive levels.
- Key pain-related genes were downregulated, while axon regeneration genes were upregulated by LMK235.
- LMK235 reduced TG neuronal excitability and reversed established pain hypersensitivity and associated behaviors.
Conclusions:
- HDAC5 is a critical epigenetic factor in the persistence of chronic trigeminal neuropathic pain.
- Post-treatment with the HDAC5 inhibitor LMK235 restores molecular balance and neuronal function.
- LMK235 demonstrates therapeutic potential for treating established chronic neuropathic pain and related comorbidities.
