TRPV4-Mediated Anti-nociceptive Effect of Suberanilohydroxamic Acid on Mechanical Pain

Abstract

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 24h 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.