HDAC inhibitors restore C‐fibre sensitivity in experimental neuropathic pain model

• Published in: British journal of pharmacology 2013-11, Vol.170 (5), p.991-998
• Main Authors: Matsushita, Yosuke, Araki, Kohei, Omotuyi, Olaposi idowu, Mukae, Takehiro, Ueda, Hiroshi
• Format: Article
• Language: English
• Subjects: Acetylation; Analgesics - pharmacology; Animals; Chromatin; Chromatin Assembly and Disassembly - drug effects; Disease Models, Animal; Epigenesis, Genetic - drug effects; Epigenetics; Ganglia, Spinal - drug effects; Ganglia, Spinal - enzymology; Ganglia, Spinal - physiopathology; HDAC inhibitor; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Histones - metabolism; Hydroxamic Acids - pharmacology; Hypesthesia - drug therapy; Hypesthesia - enzymology; Hypesthesia - genetics; Hypesthesia - physiopathology; hypoesthesia; Ligation; Male; Mice; Mice, Inbred C57BL; Nav1.8; NAV1.8 Voltage-Gated Sodium Channel - drug effects; NAV1.8 Voltage-Gated Sodium Channel - genetics; NAV1.8 Voltage-Gated Sodium Channel - metabolism; Nerve Fibers, Unmyelinated - drug effects; Nerve Fibers, Unmyelinated - enzymology; neuropathic pain; Pain; Pain Measurement; Pain Threshold - drug effects; Research Papers; Sciatic Nerve - drug effects; Sciatic Nerve - physiopathology; Sciatic Nerve - surgery; Sciatic Neuropathy - drug therapy; Sciatic Neuropathy - enzymology; Sciatic Neuropathy - genetics; Sciatic Neuropathy - physiopathology; Time Factors; Valproic Acid - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12366

Background and Purpose Hypoesthesia is a clinical feature of neuropathic pain. The feature is partly explained by the evidence of epigenetic repression of Nav1.8 sodium channel in the dorsal root ganglion (DRG). Experimental Approach We investigated the possibility of trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to reverse the unique C‐fibre sensitivity observed following partial ligation of sciatic nerve in mice. Key Results Nerve injury‐induced down‐regulation of DRG Nav1.8 sodium channel and C‐fibre‐related hypoesthesia were reversed by TSA, VPA and SAHA treatments, which inhibit histone deacetylase (HDAC), and increase histone acetylation at the regulatory sequence of Nav1.8. Conclusions and Implications Taken together, these studies provide the evidence that hypoesthesia and underlying down‐regulation of Nav1.8, negative symptoms observed in nerve injury‐induced neuropathic pain models are regulated by an epigenetic chromatin remodelling through HDAC‐related machineries.