Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model

Abstract

Chronic orofacial pain is a significant health problem requiring identification of regulating processes. Involvement of epigenetic modifications that is reported for hindlimb neuropathic pain experimental models, however, is less well studied in cranial nerve pain models. Three independent observations reported here are the (1) epigenetic profile in mouse trigeminal ganglia (TG) after trigeminal inflammatory compression (TIC) nerve injury mouse model determined by gene expression microarray, (2) H3K9 acetylation pattern in TG by immunohistochemistry, and (3) efficacy of histone deacetylase (HDAC) inhibitors to attenuate development of hypersensitivity. After TIC injury, ipsilateral whisker pad mechanical sensitization develops by day 3 and persists well beyond day 21 in contrast to sham surgery. Global acetylation of H3K9 decreases at day 21 in ipsilateral TG . Thirty-four genes are significantly (p < 0.05) overexpressed in the ipsilateral TG by at least two-fold at either 3 or 21 days post-trigeminal inflammatory compression injury. The three genes most overexpressed three days post-trigeminal inflammatory compression nerve injury are nerve regeneration-associated gene ATF3, up 6.8-fold, and two of its regeneration-associated gene effector genes, Sprr1a and Gal, up 174- and 25-fold, respectively. Although transcription levels of 25 of 32 genes significantly overexpressed three days post-trigeminal inflammatory compression return to constitutive levels by day 21, these three regeneration-associated genes remain significantly overexpressed at the later time point. On day 21, when tissues are healed, other differentially expressed genes include 39 of the top 50 upregulated and downregulated genes. Remarkably, preemptive manipulation of gene expression with two HDAC inhibitors (HDACi's), suberanilohydroxamic acid (SAHA) and MS-275, reduces the magnitude and duration of whisker pad mechanical hypersensitivity and prevents the development of a persistent pain state. These findings suggest that trigeminal nerve injury leads to epigenetic modifications favoring overexpression of genes involved in nerve regeneration and that maintaining transcriptional homeostasis with epigenetic modifying drugs could help prevent the development of persistent pain.

Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression

“…Though controversies still exist, upregulated HDACs and resultant downregulation of histone acetylation were believed to facilitate pathological pain and opioid-insensitive status in the majority of studies (Uchida et al, 2010; Denk et al, 2013; Matsushita et al, 2013; Cherng et al, 2014). Accordingly, several kinds of HDAC inhibitors, including TSA, SAHA, sodium butyrate, MS-275, and LG325 exert analgesic effects in multiple pain models (Agudelo et al, 2011; Denk et al, 2013; Kukkar et al, 2014; Hou et al, 2017; Sanna et al, 2017; Danaher et al, 2018; Liao et al, 2018; Sanna and Galeotti, 2018; Zhao and Wu, 2018).…”

Identification of Candidate Genes Involved in Renal Ischemia/Reperfusion Injury

“…In contrast, SPRR1A , another member of SPRR family, is well profiled and is known to be associated with many diseases, such as breast cancer and diffuse large B cell lymphoma (Zhang et al , 2014 ; Chen et al , 2015 ). SPRR1A is a gene related with tissue regeneration (Gaudet et al , 2016 ; Gey et al , 2016 ; Danaher et al , 2018 ) and can be controlled by ATF3 (Danaher et al , 2018 ). In the present study, we found an increased expression of SPRR1A in kidneys of IRI-treated mice.…”

Trigeminal neuropathic pain is alleviated by inhibition of Cav3.3 T-type calcium channels in mice

“…Previous studies have indicated that changes at the transcriptional level of the dorsal root or trigeminal ganglia may underlie the pathophysiology of neuropathic pain in several animal models [6][7][8]. Therefore, in order to determine the changes that may be occurring at the transcriptional level in FRICT-ION mice compared to control, we analyzed trigeminal ganglia (TG) gene expression by RNAseq 10 weeks after nerve injury.…”