TRPV4-Mediated Anti-nociceptive Effect of Suberanilohydroxamic Acid on Mechanical Pain
Biological effects of suberanilohydroxamic acid (SAHA) have mainly been observed in the context of tumor suppression via epigenetic mechanisms, but other potential outcomes from its use have also been proposed in different fields such as pain modulation. Here, we tried to understand whether SAHA modulates specific pain modalities by a non-epigenetic unknown mechanism. From 24 h Complete Freund’s Adjuvant (CFA)-inflamed hind paws of mice, mechanical and thermal inflammatory pain indices were collected with or without immediate intraplantar injection of SAHA. To examine the action of SAHA on sensory receptor-specific pain, transient receptor potential (TRP) ion channel-mediated pain indices were collected in the same manner of intraplantar treatment. Activities of primarily cultured sensory neurons and heterologous cells transfected with TRP channels were monitored to determine the molecular mechanism underlying the pain-modulating effect of SAHA. As a result, immediate and localized pretreatment with SAHA, avoiding an epigenetic intervention, acutely attenuated mechanical inflammatory pain and receptor-specific pain evoked by injection of a TRP channel agonist in animal models. We show that a component of the mechanisms involves TRPV4 inhibition based on in vitro intracellular Ca2+ imaging and electrophysiological assessments with heterologous expression systems and cultured sensory neurons. Taken together, the present study provides evidence of a novel off-target action and its mechanism of SAHA in its modality-specific anti-nociceptive effect and suggests the utility of this compound for pharmacological modulation of pain.
KeywordsSAHA Pain TRPV4 Non-epigenetic mechanism
This work was supported by grants from the National Research Foundation of Korea (2017R1A2B2001817 and 2017M3C7A1025600) and Korea Health technology R&D Project of Ministry of Health & Welfare (HI15C2099).
GC and TJY carried out the experiments and analyzed the data. TJY and GC wrote the preliminary draft. SY, SIC, JYL, and PSC assisted the experiments and contributed to the result interpretations. SWH supervised the studies and wrote the manuscript. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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