Jing Xu1, Yi-Wei Feng, Ling Liu, Wei Wang, Xiong-Xiong Zhong, Xu-Hong Wei, Xian-Guo Liu. 1. From the Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China (J.X., Y.-W.F., W.W., X.-X.Z., X.-H.W., X.-G.L.); Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, People's Republic of China (X.-H.W., X.-G.L.); and Department of Anesthesiology, Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, People's Republic of China (L.L.).
Abstract
BACKGROUND: Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown. METHODS: A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms. RESULTS: Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-α (mean ± SD: 196 ± 48 vs. 119 ± 57; n = 6; P < 0.01) and interleukin 1β (mean ± SD: 215 ± 69 vs. 158 ± 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor α mutation. Moreover, more glial cells were activated, and more interleukin 1β was released in the spinal dorsal horn in liver X receptor α knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines. CONCLUSIONS: Activation of liver X receptor α inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids.
BACKGROUND: Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown. METHODS: A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms. RESULTS: Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-α (mean ± SD: 196 ± 48 vs. 119 ± 57; n = 6; P < 0.01) and interleukin 1β (mean ± SD: 215 ± 69 vs. 158 ± 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor α mutation. Moreover, more glial cells were activated, and more interleukin 1β was released in the spinal dorsal horn in liver X receptor α knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines. CONCLUSIONS: Activation of liver X receptor α inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids.