BackgroundNeuropathic pain remains a formidable challenge for modern medicine. The first-line pharmacological therapies exhibit limited efficacy and unfavorable side effect profiles, highlighting an unmet need for effective therapeutic medications. The past decades have witnessed an explosion in efforts to translate epigenetic concepts into pain therapy and shed light on epigenetics as a promising avenue for pain research. Recently, the aberrant activity of histone deacetylase (HDAC) has emerged as a key mechanism contributing to the development and maintenance of neuropathic pain.AimsIn this review, we highlight the distinctive role of specific HDAC subtypes in a cell-specific manner in pain nociception, and outline the recent experimental evidence supporting the therapeutic potential of HDACi in neuropathic pain.MethodsWe have summarized studies of HDAC in neuropathic pain in Pubmed.ResultsHDACs, widely distributed in the neuronal and non-neuronal cells of the dorsal root ganglion and spinal cord, regulate gene expression by deacetylation of histone or non-histone proteins and involving in increased neuronal excitability and neuroinflammation, thus promoting peripheral and central sensitization. Importantly, pharmacological manipulation of aberrant acetylation using HDAC-targeted inhibitors (HDACi) has shown promising pain-relieving properties in various preclinical models of neuropathic pain. Yet, many of which exhibit low-specificity that may induce off-target toxicities, underscoring the necessity for the development of isoform-selective HDACi in pain management.ConclusionsAbnormally elevated HDACs promote neuronal excitability and neuroinflammation by epigenetically modulating pivotal gene expression in neuronal and immune cells, contributing to peripheral and central sensitization in the progression of neuropathic pain, and HDACi showed significant efficacy and great potential for alleviating neuropathic pain. Histone acetylation modification is governed by the intricate interplay of histone deacetylases (HDACs) and histone acetyltransferases (HATs), where elevated HDAC activity in both neurons and immune cells regulates the expression of genes implicated in pain pathways, promoting neuronal excitability and neuroinflammation, and ultimately, enabling neuropathic pain.image