Comparison of Different Histone Deacetylase Inhibitors in Attenuating Inflammatory Pain in Rats

Abstract

Histone deacetylase inhibitors (HDACIs), which interfere with the epigenetic process of histone acetylation, have shown analgesic effects in animal models of persistent pain. The HDAC family comprises 18 genes; however, the different effects of distinct classes of HDACIs on pain relief remain unclear. The aim of this study was to determine the efficacy of these HDACIs on attenuating thermal hyperalgesia in persistent inflammatory pain. Persistent inflammatory pain was induced by injecting Complete Freund's Adjuvant (CFA) into the left hind paw of rats. Then, HDACIs targeting class I (entinostat (MS-275)) and class IIa (sodium butyrate, valproic acid (VPA), and 4-phenylbutyric acid (4-PBA)), or class II (suberoylanilide hydoxamic acid (SAHA), trichostatin A (TSA), and dacinostat (LAQ824)) were administered intraperitoneally once daily for 3 or 4 days. We found that the injection of SAHA once a day for 3 days significantly attenuated CFA-induced thermal hyperalgesia from day 4 and lasted 7 days. In comparison with SAHA, suppression of hyperalgesia by 4-PBA peaked on day 2, whereas that by MS-275 occurred on days 5 and 6. Fatigue was a serious side effect seen with MS-275. These findings will be beneficial for optimizing the selection of specific HDACIs in medical fields such as pain medicine and neuropsychiatry.

Figure 1

Flow chart of the study evaluating the effects of HDACIs on thermal hyperalgesia in rats.

Figure 2

Attenuation of effects of postinjected HDACIs on thermal hyperalgesia in rats. Rat received injection of HDACI or vehicle (arrows show the time of injection) at the indicated dose after unilateral intraplantar injection of CFA. PWL was determined before CFA injection as a baseline and after CFA injection as hyperalgesia response. SAHA (a), TSA (b), LAQ824 (c), sodium butyrate (d), 4-PBA (e), VPA (f), and MS-275 (g) were injected for the panel (in parenthesis). Inhibition of hyperalgesia by all HDACIs was calculated by two-way ANOVA. Data show PWL as the mean ± SEM for the ipsilateral paw (^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001 compared with vehicle-treated rats at the same time point).

Figure 3

Comparison of SAHA with other tested HDACIs in inhibition of thermal hyperalgesia after intraplantar injection of CFA. Inhibition of hyperalgesia by all HDACIs displayed from the second to sixth day after CFA injection was calculated using one-way ANOVA. Data show PWL as the mean ± SEM for the ipsilateral paw (∗p < 0.05, and ∗∗∗p < 0.001 compared with SAHA-treated rats at the same time point).