Histone deacetylase 2 is involved in �‑opioid receptor suppression in the spinal dorsal horn in a rat model of chronic pancreatitis pain

Abstract

Chronic pain occurs in ~85–90% of chronic pancreatitis (CP) patients. However, as the pathogenesis of CP pain remains to be fully understood, the current therapies for CP pain remain inadequate. Emerging evidence has suggested that the epigenetic modulations of genes are involved in chronic pain. In the present study, intrapancreatic trinitrobenzene sulfonic acid infusions were used to establish a CP model in rats. Mechanical allodynia was measured with von Frey filaments. Immunofluorescent staining analysis was used to observe the expression changes of histone deacetylase 2 (HDAC2) and µ-opioid receptor (MOR), and intrathecal administration of the selective HDAC2 inhibitor AR-42 was used to assess the underlying mechanisms. The expression levels of c-Jun N-terminal kinase (JNK) in the thoracic spinal cord were detected by western blotting, and the mRNA expression levels of interleukin (IL)1-β, IL-6 and tumor necrosis factor (TNF)-α were detected by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that HDAC2 expression was upregulated during the course of CP induction, while MOR activity in the thoracic spinal dorsal horn was significantly suppressed. Intrathecal infusion of AR-42 significantly attenuated CP-induced mechanical allodynia, with rescued MOR activity. Additionally, HDAC2 facilitated the release of inflammatory cytokines, including IL-1β, IL-6 and TNF-α. These results suggested that the underlying mechanisms of HDAC2 regulating MOR activity under CP induction may occur via promoting the release of inflammatory cytokines, thus activating the JNK signaling pathway. The present study suggested that the epigenetic-regulated disturbance of MOR is dependent on the endogenous analgesia system in CP, which may a provide novel therapeutic strategy for treating pain in CP.

Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia

“…We also found that SAHA administration could not affect basal HDACs of the Sham group ( Fig. 6c-e), which agreed with previously published researches [48]. Other studies have also indicated that SAHA can selectively alters the transcription of relatively few genes, and normal cells are at least ten fold more resistant than transformed cells to SAHA and related HDAC inhibitor-induced cell death (for example, see [49]).…”

Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats

“…The different effects of SAHA on opioid-induced pain behavior might be due to different pathological conditions. Liang et al studied the effects of SAHA on morphine-induced hyperalgesia in normal conditions ( Liang et al, 2013 ), while our study and those by other researchers examined the effects of SAHA on morphine tolerance in the pathogenesis of chronic pain ( Hou et al, 2017 ; Liao et al, 2018 ). HDAC expression and histone acetylation in pathological conditions may be quite different from those in physiological conditions.…”

“…The effects of HDACi on morphine tolerance are controversial. Some studies have indicated that HDACi can enhance the analgesic effects of morphine and attenuate morphine tolerance ( Dobashi et al, 2010 ; Tsai et al, 2016 ; Hou et al, 2017 ; Liao et al, 2018 ). However, some studies have demonstrated that chronic morphine treatment with simultaneous SAHA treatment can enhance opioid-induced hyperalgesia ( Liang et al, 2013 ).…”

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).…”

“…Another study found that chronic fluoxetine treatment induced a sex-dependent analgesic effect, and this phenomenon may be mediated by HDAC2 repression and incremental mGlu2 receptor expression in the spinal cord dorsal horn of female mice (Zammataro et al, 2017). Recently, participation of HDAC2 in bone cancer pain and chronic pancreatitis pain was proposed, as a favorable pain-relieving effect was observed after HDAC2 knockdown or inhibition (Hu et al, 2017; Hou et al, 2018; Liao et al, 2018). In the present study, we found that HDAC2 mRNA and protein levels were both elevated after sciatic nerve constriction.…”