Systemic QX-314 Reduces Bone Cancer Pain through Selective Inhibition of Transient Receptor Potential Vanilloid Subfamily 1-expressing Primary Afferents in Mice
Systemic QX-314 Reduces Bone Cancer Pain through Selective Inhibition of Transient Receptor Potential Vanilloid Subfamily 1-expressing Primary Afferents in Mice
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DOI：
10.1097/aln.0000000000001152
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发表时间：
2016-07-01
期刊：
影响因子：
8.8
通讯作者：
Kawamata, Mikito
中科院分区：
文献类型：
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作者：
Fuseya, Satoshi;Yamamoto, Katsumi;Kawamata, Mikito
背景资料：本研究的目的是确定全身给药QX-314是否通过选择性抑制瞬时受体电位香草酸亚家族1（TRPV 1）表达afferends.Methods：骨癌疼痛的小鼠模型，减少骨癌疼痛。作者检查了大剂量的影响，（0.01 - 3 mg/kg，n = 6 - 10）和连续给药（5 mg kg（-1）h（-1），n = 5）给予QX-314对骨癌疼痛相关行为和背根神经节神经元中磷酸化环磷酸腺苷反应元件结合蛋白表达的影响结果：在10 min时，QX-314处理组小鼠持续疼痛的退缩次数少于溶剂处理组（3 mg/kg，4 +/- 3; 1 mg/kg，5 +/- 3 vs. 12 +/- 3; P < 0.001; n = 8至9），24 h（3 +/- 2 vs. 13 +/- 3，P < 0.001），48 h（4 +/- 1 vs. 12 +/- 2，P < 0.001;每组n = 5），但肢体使用受损，包括通过CatWalk系统检查的负重，和指示运动诱发疼痛的旋转棒性能是相当的。与溶剂给药相比，QX-314选择性抑制TRPV 1阳性背根神经节神经元中磷酸化环磷酸腺苷反应元件结合蛋白表达的增加，但不抑制TRPV 1阴性背根神经节神经元中磷酸化环磷酸腺苷反应元件结合蛋白表达的增加（32.2 +/- 3.0% vs. 52.6 +/-5.9%，P < 0.001;每组n = 6）。结论：全身给予QX-314可通过选择性抑制TRPV 1的传入神经而抑制骨癌痛小鼠的某些行为学方面，而无需同时给予TRPV 1激动剂。
Background: The aim of this study was to determine whether systemic administration of QX-314 reduces bone cancer pain through selective inhibition of transient receptor potential vanilloid subfamily 1 (TRPV1)-expressing afferents.Methods: A mouse model of bone cancer pain was used. The authors examined the effects of bolus (0.01 to 3 mg/kg, n = 6 to 10) and continuous (5 mg kg(-1) h(-1), n = 5) administration of QX-314 on both bone cancer pain-related behaviors and phosphorylated cyclic adenosine monophosphate response element-binding protein expression in dorsal root ganglion neurons (n = 3 or 6) and the effects of ablation of TRPV1-expressing afferents on bone cancer pain-related behaviors (n = 10).Results: The numbers of flinches indicative of ongoing pain in QX-314-treated mice were smaller than those in vehicle-treated mice at 10 min (3 mg/kg, 4 +/- 3; 1 mg/kg, 5 +/- 3 vs. 12 +/- 3; P < 0.001; n = 8 to 9), 24 h (3 +/- 2 vs. 13 +/- 3, P < 0.001), and 48 h (4 +/- 1 vs. 12 +/- 2, P < 0.001; n = 5 in each group) after QX-314 administration, but impaired limb use, weight-bearing including that examined by the CatWalk system, and rotarod performance indicative of movement-evoked pain were comparable. QX-314 selectively inhibited the increase in phosphorylated cyclic adenosine monophosphate response elementbinding protein expression in TRPV1-positive, but not in TRPV1-negative, dorsal root ganglion neurons compared to that in the case of vehicle administration (32.2 +/- 3.0% vs. 52.6 +/- 5.9%, P < 0.001; n = 6 in each group). Ablation of TRPV1expressing afferents mimicked the effects of QX-314.Conclusion: This study showed that systemic administration of QX-314 in mice inhibits some behavioral aspects of bone cancer pain through selective inhibition of TRPV1-expressing afferents without coadministration of TRPV1 agonists.