Abstract
The easily developed morphine tolerance in bone cancer pain (BCP) significantly hindered its clinical use. Increasing evidence suggests that histone deacetylases (HDACs) regulate analgesic tolerance subsequent to continuous opioid exposure. However, whether HDACs contribute to morphine tolerance in the pathogenesis of BCP is still unknown. In the current study, we explored the possible engagement of HDACs in morphine tolerance during the pathogenesis of BCP. After intra-tibia tumor cell inoculation (TCI), we found that the increased expression of HDACs was negatively correlated with the decreased expression of MOR in the DRG following TCI. The paw withdrawal threshold (PWT) and percentage maximum possible effects (MPEs) decreased rapidly in TCI rats when morphine was used alone. In contrast, the concomitant use of SAHA and morphine significantly elevated the PWT and MPEs of TCI rats compared to morphine alone. Additionally, we found that SAHA administration significantly elevated MOR expression in the DRG of TCI rats with or without morphine treatment. Moreover, the TCI-induced increase in the co-expression of MOR and HDAC1 in neurons was significantly decreased after SAHA administration. These results suggest that HDACs are correlated with the downregulation of MOR in the DRG during the pathogenesis of BCP. Inhibition of HDACs using SAHA can be used to attenuate morphine tolerance in BCP.
Highlights
As advances in cancer therapy have extended the life expectancy of cancer patients, improving the quality of patient life is critically important (Siegel et al, 2017)
Neurons were determined as mediated by the μ-opioid receptor (MOR)/HDAC1/HDAC2 positive if the signal intensity was three-fold higher than the background using Stereo Investigator software (MicroBrightField, Williston, VT, United States)
Given that the decreased MOR expression was negatively correlated with the increased Histone deacetylases (HDACs) expression in the dorsal root ganglia (DRG) following tumor cell inoculation (TCI), we examined whether inhibition of HDACs by SAHA, a clinically used HDAC inhibitor, can attenuate morphine tolerance during the pathogenesis of bone cancer pain (BCP) (Figure 5A)
Summary
As advances in cancer therapy have extended the life expectancy of cancer patients, improving the quality of patient life is critically important (Siegel et al, 2017). Several studies have shown that MOR expression is significantly decreased in the DRG in a mouse model of BCP, whereas MOR expression in the DRG of a mouse model of inflammatory pain was unchanged (Mao et al, 1995; Yamamoto et al, 2008; Yao et al, 2016). This finding suggests that patients with BCP prone to morphine tolerance may be due to the downregulation of MOR in the DRG. We hypothesize that the downregulation of MOR in the DRG of BCP may be correlated with the increased expression of HDACs, and inhibition of HDACs could enhance MOR expression to attenuate morphine tolerance
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