Potent analgesic effects of a store-operated calcium channel inhibitor

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• 作者：Ruby Gao ; Xinghua Gao ; Jingsheng Xia ; Yuzhen Tian ; James E. Barrett ; Yue Dai ; Huijuan Hu
• 关键词：Dorsal root ganglia ; Inflammation ; Pain ; Store-operated calcium channels ; Tumor necrosis factor alpha ; YM-58483
• 刊名：Pain
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：154
• 期：10
• 页码：2034-2044
• 全文大小：565 K

文摘

Chronic pain often accompanies immune responses and immune cells are known to be involved in chronic pain. Store-operated calcium (SOC) channels are calcium-selective cation channels and play an important role in the immune system. YM-58483, a potent SOC channel inhibitor, has been shown to inhibit cytokine production from immune cells and attenuate antigen-induced hypersensitivity reactions. Here, we report that YM-58483 has analgesic actions in chronic pain and produces antinociceptive effects in acute pain and prevents the development of chronic pain in mice. Oral administration of 10 mg/kg or 30 mg/kg YM-58483 dramatically attenuated complete Freund adjuvant (CFA)-induced thermal hyperalgesia and prevented the development of thermal and mechanical hypersensitivity in a dose-dependent manner. Analgesic effects were observed when YM-58483 was administered systemically, intrathecally and intraplantarly. YM-58483 decreased spared nerve injury (SNI)-induced thermal and mechanical hypersensitivity and prevented the development of SNI-induced pain hypersensitivity. Pretreatment with YM-58483 strongly reduced both the first and second phases of formalin-induced spontaneous nocifensive behavior in a dose-dependent manner. YM-58483 produced antinociception in acute pain induced by heat or chemical or mechanical stimuli at a dose of 30 mg/kg. YM-58483 diminished CFA-induced paw edema, and reduced production of TNF-¦Á, IL-1¦Â and PGE₂ in the CFA-injected paw. In vitro, SOC entry in nociceptors was more robust than in nonnociceptors, and the inhibition of SOC entry by YM-58483 in nociceptors was much greater than in nonnociceptors. Our findings indicate that YM-58483 is a potent analgesic and suggest that SOC channel inhibitors may represent a novel class of therapeutics for pain.