Abstract
Bone cancer pain (BCP) is an intractable clinical problem, and lacked effective drugs for treating it. Recent research showed that several chemokines in the spinal cord are involved in the pathogenesis of BCP. In this study, the antinociceptive effects of liquiritin, which is an active component extracted from Glycyrrhizae Radix, were tested and the underlying mechanisms targeting spinal dorsal horn (SDH) were investigated. The BCP group displayed a significant decrease in the mechanical withdrawal threshold on days 6, 12, and 18 when compared with sham groups. Intrathecal administration of different doses of liquiritin alleviated mechanical allodynia in BCP rats. The results of immunofluorescent staining and western blotting showed that liquiritin inhibited BCP-induced activation of astrocytes in the spinal cord. Moreover, intrathecal administration of liquiritin effectively inhibited the activation of CXCL1/CXCR2 signaling pathway and production of IL-1β and IL-17 in BCP rats. In astroglial-enriched cultures, Lipopolysaccharides (LPS) elicited the release of chemokine CXCL1, and the release was decreased in a dose-dependent manner by liquiritin. In primary neurons, liquiritin indirectly reduced the increase of CXCR2 by astroglial-enriched-conditioned medium but not directly on the CXCR2 target site. These results suggested that liquiritin effectively attenuated BCP in rats by inhibiting the activation of spinal astrocytic CXCL1 and neuronal CXCR2 pathway. These findings provided evidence regarding the the antinociceptive effect of liquiritin on BCP.
Highlights
Bone cancer pain (BCP) is often severe and intractable, and has a strong effect on the quality of life of cancer patients
To verify whether treatment with astrocyte conditioned medium pre-treated with LQ that is substituted with half neuronal medium, western blotting (WB) and real-time polymerase chain reaction (RT-PCR) were performed for CXCR2, and the results showed that upregulation of neuronal CXCR2 expression has become sensitive to the effect of LQ (F4,15 = 63.6, ***P < 0.001 vs. Naive, ###P < 0.001 vs. control, F4,15 = 26.58, ***P < 0.001 vs. naïve, #P < 0.05, ###P < 0.001 vs. control; n = 4, one way analysis of variance (ANOVA), Figures 9F, G)
The present study examined the antinociceptive effects and possible underlying mechanisms of LQ in the BCP rat model
Summary
Bone cancer pain (BCP) is often severe and intractable, and has a strong effect on the quality of life of cancer patients. The activated glial cells release the proinflammatory cytokines that act on their receptors and express on postsynaptic neurons, leading to post-synaptic hyperexcitability and facilitatory pain transmission (Guo et al, 2007; Jin et al, 2018; Wang et al, 2018). Recent findings strongly suggested that CXCL1 might act on CXCR2 via glial-neuronal interactions in the spinal cord in several pathological pain models (Cao et al, 2014; Chen et al, 2014). Our recent study demonstrated that CXCL1-CXCR2 signaling plays a critical role in glial-neuron interactions and in descending facilitation of BCP (Ni et al, 2019a)
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