• Farhana Sakloth, Lefteris Manouras, Kleopatra Avrampou, Vasiliki Mitsi, Randal A Serafini, Kerri D Pryce, Valeria Cogliani, Olivier Berton, Matthew Jarpe, and Venetia Zachariou.
• Nash Family Department of Neuroscience, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, Box 10-65, New York, NY, 10029, USA.
• Psychopharmacology (Berl.). 2020 Jul 1; 237 (7): 2139-2149.

BackgroundHDAC6 is a class IIB histone deacetylase expressed at many levels of the nociceptive pathway. This study tested the ability of novel and selective HDAC6 inhibitors to alleviate sensory hypersensitivity behaviors in mouse models of peripheral nerve injury and peripheral inflammation.MethodsWe utilized the murine spared nerve injury (SNI) model for peripheral nerve injury and the Complete Freund's Adjuvant (CFA) model of peripheral inflammation. We applied the Von Frey assay to monitor mechanical allodynia.ResultsUsing the SNI model, we demonstrate that daily administration of the brain-penetrant HDAC6 inhibitor, ACY-738, abolishes mechanical allodynia in male and in female mice. Importantly, there is no tolerance to the antiallodynic actions of these compounds as they produce a consistent increase in Von Frey thresholds for several weeks. We observed a similar antiallodynic effect when utilizing the HDAC6 inhibitor, ACY-257, which shows limited brain expression when administered systemically. We also demonstrate that ACY-738 and ACY-257 attenuate mechanical allodynia in the CFA model of peripheral inflammation.ConclusionsOverall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation.

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