Suppression of Peripheral Pain by Blockade of Voltage-Gated Calcium 2.2 Channels in Nociceptors Induces RANKL and Impairs Recovery From Inflammatory Arthritis in a Mouse Model.
Suppression of Peripheral Pain by Blockade of Voltage-Gated Calcium 2.2 Channels in Nociceptors Induces RANKL and Impairs Recovery From Inflammatory Arthritis in a Mouse Model.
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DOI：
10.1002/art.39094
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发表时间：
2015-06
影响因子：
13.3
通讯作者：
Ibanez-Tallon, Ines
中科院分区：
文献类型：
--
作者：
Baddack, Uta;Frahm, Silke;Antolin-Fontes, Beatriz;Grobe, Jenny;Lipp, Martin;Mueller, Gerd;Ibanez-Tallon, Ines
类风湿性关节炎（RA）的一个标志是伴随炎症和关节变形的慢性疼痛。RA患者疼痛缓解率最高，然而，很少有研究涉及专门针对疼痛通路的治疗的疗效和安全性。芋螺毒素MVIIA（Prialt/Ziconotide）用于人类缓解持续性疼痛综合征，因为它特异性阻断CaV2.2电压门控钙通道，介导神经递质和促炎介质从外周伤害感受器神经末梢释放。本研究的目的是研究阻断CaV2.2是否可以抑制关节炎疼痛，并检查持续CaV2.2阻断期间诱导的关节炎的进展。使用在伤害感受器特异性基因控制下表达膜系留形式的ω-芋螺毒素MVIIA的转基因小鼠（Tg-MVIIA）。使用抗原和胶原诱导的关节炎（ACIA）模型对这些小鼠进行关节炎症的单侧诱导。我们观察到由t-MVIIA介导的CaV2.2阻断有效抑制关节炎诱导的疼痛;然而，与其野生型同窝小鼠相反，随着炎症消退，其最终恢复使用其受损的关节，Tg-MVIIA小鼠显示持续的炎症，伴随破骨细胞激活剂RANKL的上调以及伴随的关节和骨破坏。总之，我们的研究结果表明，通过阻断CaV2.2介导的钙离子内流和伤害感受器感觉神经元中的信号传导来缓解外周疼痛，会损害诱导性关节炎的恢复，并指出在炎症期间使用CaV2.2通道阻断剂作为镇痛剂的潜在破坏性影响。
A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies the inflammation and joint deformation. Patients with RA rate pain relief with highest priority, however, few studies have addressed the efficacy and safety of therapies directed specifically towards pain pathways. The conotoxin MVIIA (Prialt/Ziconotide) is used in humans to alleviate persistent pain syndromes because it specifically blocks the CaV2.2 voltage-gated calcium channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The purpose of this study was to investigate whether block of CaV2.2 can suppress arthritic pain, and to examine the progression of induced arthritis during persistent CaV2.2 blockade. Transgenic mice (Tg-MVIIA) expressing a membrane-tethered form of the ω-conotoxin MVIIA, under the control of a nociceptor-specific gene, were employed. These mice were subjected to unilateral induction of joint inflammation using the Antigen- and Collagen-Induced Arthritis (ACIA) model. We observed that CaV2.2-blockade mediated by t-MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsides, Tg-MVIIA mice showed continued inflammation with an up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. Altogether, our results indicate that alleviation of peripheral pain by blockade of CaV2.2- mediated calcium influx and signaling in nociceptor sensory neurons, impairs recovery from induced arthritis and point to the potentially devastating effects of using CaV2.2 channel blockers as analgesics during inflammation.
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影响因子：
7.4
作者：
Kilo, S;HardingRose, C;Flores, CM
通讯作者：
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影响因子：
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作者：
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作者：
Auer, Sebastian;Stuerzebecher, Annika S.;Ibanez-Tallon, Ines
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作者：
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作者：
Just, S;Heppelmann, B
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