HDAC6 inhibition ameliorates sensory hypersensitivity and reduces immune cell signatures in the dorsal root ganglia in murine chronic pain models.

Histone deacetylase (HDAC)6 is a broadly expressed class IIb HDAC that regulates cytoskeletal dynamics and some nuclear processes. Previously research has shown that HDAC6 enzymatic inhibition has analgesic properties in models of chemotherapy-induced peripheral neuropathy. Here, we evaluated the effects of genetic and pharmacologic inhibition of HDAC6 on the development of sensory hypersensitivity in mouse models of peripheral nerve injury and peripheral inflammation. Daily administration of the peripherally restricted HDAC6 inhibitor, ACY1215 (Regenacy Pharmaceuticals, Inc), attenuated mechanical allodynia in the von Frey assay within 2 days of treatment initiation, with no signs of analgesic tolerance after 21 days of administration. We observed a similar antiallodynic effect across the implemented injury models after conditionally knocking down Hdac6 in the adult dorsal root ganglia (DRGs). Bioinformatic analysis of whole-transcriptome RNA-sequencing data predicted that ACY1215 treatment predominantly attenuated proinflammatory mechanisms, such as the suppression of immune cell infiltration into the DRG after injury. Accordingly, we demonstrated a reduction in the expression of various immune cell markers in the DRG after pharmacologic and genetic HDAC6 inhibition in both neuropathic and inflammatory pain models. We identified a direct relationship between Ccl5/Ccr5 and Hdac6 downregulation, as well as reduced hypersensitivity after hind paw CCL5 administration upon Hdac6 knockdown in the DRG. Our findings highlight that peripheral inhibition of HDAC6 ameliorates sensory hypersensitivity in models of postoperative inflammatory and neuropathic pain through mechanisms beyond reduction of tubulin deacetylation. SIGNIFICANCE STATEMENT: Recent studies highlight the role of histone deacetylase (HDAC)6 in chemotherapy-induced peripheral neuropathy, through mechanisms of action including tubulin acetylation and mitochondrial trafficking. In this study, various murine models of acute and chronic pain are applied to show that inhibition of HDAC6 activity in the periphery, using the clinically tested ACY1215 compound, and genetic inactivation of the Hdac6 gene in the dorsal root ganglia, alleviated mechanical hypersensitivity in male and in female mice through mechanisms that include targeting injury-induced inflammation.