HDAC Inhibitors Attenuate Hypersensitivity in Models of Orofacial Neuropathic Pain

Objectives: Chronic orofacial pain (OFP) is a significant health problem afflicting millions of persons in the US. Chronic OFP occurs when a biological process becomes ‘locked’ in an improper pattern. Identification of this process and understanding why it cannot return to a resting pattern is important for developing new drugs that target this process. Recent evidence suggests that epigenetic mechanisms are involved in maintaining chronic pain states. Identification of genes critical to development of a persisting pain state and the molecular basis for such dysregulation would lead to targeted pharmacological treatment directed at the cause rather than the symptoms.
Methods: Gene expression patterns in trigeminal ganglia (TG) were determined using microarray technology to identify differentially expressed genes in a mouse neuropathic OFP model at two time points. To identify evidence of epigenetic changes associated with establishment of orofacial pain, we examined the expression of H3K9 acetylation patterns in TG by immunohistochemistry and the ability of histone deacetylase inhibitor (HDAC) inhibitors (MS275, SAHA) to attenuate mechanical hypersensitivity using our novel trigeminal inflammatory compression (TIC) mouse model of neuropathic OFP.
Results: We determined that many genes in the TG are differentially expressed following TIC injury. Moreover, inhibition of H3K9 deacetylation before and shortly after nerve injury with SAHA or MS275 prevented development of OFP.
Conclusions: Identifying genes critical in OFP and the basis of their dysregulation will lead to novel avenues for therapeutic intervention.