Histone deacetylase inhibitors (HDACi) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain [1-3]. This study set out to determine whether these compounds could also impact neuropathic pain. Different class I HDACi were delivered intrathecally to rat spinal cord in models of traumatic nerve injury and antiretroviral drug induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40-50% as a result of HDACi treatment, but only if commenced prior to any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia (DRG) in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence and/or maintenance of neuropathic pain.