Current treatments for
neuropathic pain have often moderate efficacy and present unwanted effects showing the need to develop effective
therapies. Accumulating evidence suggests that
histone acetylation plays essential roles in
chronic pain and the
analgesic activity of
histone deacetylases (HDACs) inhibitors is documented. Bromodomain and extra-terminal domain (BET)
proteins are epigenetic readers that interact with acetylated
lysine residues on
histones, but little is known about their implication in
neuropathic pain. Thus, the current study was aimed to investigate the effect of the combination of HDAC and BET inhibitors in the spared nerve injury (SNI) model in mice.
Intranasal administration of
i-BET762 (BET inhibitor) or SAHA (
HDAC inhibitor) attenuated thermal and mechanical
hypersensitivity and this antiallodynic activity was improved by co-administration of both drugs. Spinal cord sections of SNI mice showed an increased expression of HDAC1 and Brd4
proteins and combination produced a stronger reduction compared to each epigenetic agent alone. SAHA and
i-BET762, administered alone or in combination, counteracted the SNI-induced microglia activation by inhibiting the expression of IBA1, CD11b,
inducible nitric oxide synthase (iNOS), the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-1 (STAT1) with comparable efficacy. Conversely, the epigenetic inhibitors showed a modest effect on spinal proinflammatory
cytokines content that was significantly potentiated by their combination. Present results indicate a key role of acetylated
histones and their recruitment by BET
proteins on microglia-mediated spinal
neuroinflammation. Targeting
neuropathic pain with the combination of HDAC and BET inhibitors may represent a promising new therapeutic option.