Alpha-Asarone Alleviated Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition Of Spinal Endoplasmic Reticulum Stress In An Liver X Receptor-Dependent Manner

BACKGROUND: Neuropathic pain is an intractable and complex disease. Recent studies have shown a close relationship between endoplasmic reticulum (ER) stress and neuropathic pain. Here, we investigated the effect of alpha-asarone, an ER stress inhibitor, on chronic constriction injury (CCI)-induced neuropathic pain.METHODS: Two parts were included in this study. In part 1, rats were assigned to 7 groups: the sham group, the sham + alpha-asarone 20 mg/kg group, the CCI group, the CCI + vehicle group, the CCI + alpha-asarone 5 mg/kg group, the CCI + alpha-asarone 10 mg/kg group, and the CCI + alpha-asarone 20 mg/kg group. After surgery, the rats were treated with alpha-asarone or normal saline daily. Pain thresholds were measured, and samples of the L3-6 spinal cord were taken for western blotting and immunofluorescence on day 7. In part 2, rats were intrathecally implanted with PE-10 tubes and divided into 4 groups: the CCI + alpha-asarone 20 mg/kg group, the CCI + alpha-asarone 20 mg/kg + vehicle group, the CCI + alpha-asarone 20 mg/kg + SR9243 group, and the CCI group. Five rats in each group were separated for behavioral tests 1 hour after intrathecal injection. The rest of them were killed for western blotting on day 7.RESULTS: In this study, CCI surgery significantly induced mechanical allodynia and thermal hyperalgesia. CCI surgery significantly induced activation of ER stress (PERK-eIF2 alpha, IRE1 alpha, CHOP, and XBP-1s) in rats. However, treatment with 20 mg/kg of alpha-asarone significantly alleviated CCIinduced activation of ER stress. Behavioral results showed that daily treatment with 20 mg/kg of alpha-asarone significantly alleviated CCI-induced nociceptive behaviors, on day 7 (mechanical allodynia, P = .016, 95% confidence interval, 0.645-5.811; thermal hyperalgesia, P = .012, 95% confidence interval, 0.860-6.507). Furthermore, alpha-asarone induced upregulated expression of liver X receptor beta (LXR beta) and downstream proteins in the spinal cord. The LXR antagonist SR9243 completely inhibited the anti-ER stress and antinociceptive effects of alpha-asarone in rats.CONCLUSIONS: alpha-Asarone relieved CCI-induced neuropathic pain in an LXR-dependent manner. alpha-Asarone may be a potential agent for treatment of neuropathic pain.