Antiallodynic effect of etidronate, a bisphosphonate, in rats with adjuvant-induced arthritis:: Involvement of ATP-sensitive K+ channels
Antiallodynic effect of etidronate, a bisphosphonate, in rats with adjuvant-induced arthritis:: Involvement of ATP-sensitive K+ channels
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DOI：
10.1016/j.neuropharm.2006.03.015
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发表时间：
2006-08-01
影响因子：
4.7
通讯作者：
Sekiguchi, Fumiko
中科院分区：
文献类型：
--
作者：
Kawabata, Atsufumi;Kawao, Naoyuki;Sekiguchi, Fumiko
双膦酸盐、焦磷酸盐类似物，被称为骨吸收抑制剂，似乎可以在某些临床疼痛情况下产生镇痛作用。为了检测依替膦酸盐（一种非氨基二膦酸盐）的临床相关镇痛特性，我们检查并表征了其对佐剂诱导性关节炎大鼠的抗异常疼痛作用，并与阿仑膦酸盐（一种氨基二膦酸盐）进行比较，通过冯弗雷试验确定。以 10-40 mg/kg/天重复全身给药依替膦酸可抑制佐剂诱导的大鼠后爪机械异常性疼痛，效果在大约 10 天内达到稳定水平。全身或足底内 (i.pl.) 给予 ATP 敏感的 K+ (K-ATP(+)) 通道抑制剂、格列本脲和/或甲苯磺丁脲，可在 1 小时内完全逆转关节炎大鼠中依替膦酸的抗异常疼痛作用，且不影响未接受依替膦酸的幼稚或关节炎动物的伤害性评分。反复服用阿仑膦酸钠也显示出类似的格列本脲可逆性抗异常疼痛作用。相反，反复全身性吲哚美辛的抗异常疼痛作用对 i.pl 具有抵抗力。格列本脲在关节炎大鼠中的作用。重复施用依替膦酸钠或阿仑膦酸钠仅略微减轻佐剂引起的后爪水肿。 K-ATP(+)通道亚基中，大鼠背根神经节中Kir6.1、SUR1、SUR2A和SUR2B mRNA丰富，而Kir6.2 mRNA含量较少。我们的数据表明，重复的依替膦酸和阿仑膦酸在关节炎大鼠中表现出抗异常疼痛活性，这可能具有临床相关性，并表明 K-ATP(+) 通道参与了潜在的机制。 (c) 2006 Elsevier Ltd. 保留所有权利。
Bisphosphonates, pyrophosphate analogues, known as inhibitors of bone resorption, appear to cause analgesia in certain clinical painful situations. To detect clinically relevant analgesic property of etidronate, a non-aminobisphosphonate, we examined and characterized its antiallodynic effect in the rat with adjuvant-induced arthritis, in comparison with alendronate, an aminobisphosphonate, as determined by the von Frey test. Repeated systemic administration of etidronate at 10-40 mg/kg/day suppressed the adjuvant-induced mechanical allodynia in rat hindpaw, an effect reaching a plateau in approximately 10 days. Systemic or intraplantar (i.pl.) administration of ATP-sensitive K+ (K-ATP(+)) channel inhibitors, glibenclamide and/or tolbutamide, completely reversed the antiallodynic effect of etidronate within 1 h in the arthritic rats, without affecting the nociceptive scores in naive or arthritic animals that had not received etidronate. Alendronate, administered repeatedly, also revealed similar glibenclamide-reversible antiallodynic effect. In contrast, the antiallodynic effect of repeated systemic indomethacin was resistant to i.pl. glibenclamide in the arthritic rats. Repeated administration of etidronate or alendronate only slightly attenuated the adjuvant-evoked hindpaw edema. Among K-ATP(+) channel subunits, mRNAs for Kir6.1, SUR1, SUR2A and SUR2B were abundant in rat dorsal root ganglia, while Kir6.2 mRNA was poor. Our data demonstrate that repeated etidronate as well as alendronate exhibits antiallodynic activity in arthritic rats, which might be clinically relevant, and suggest involvement of K-ATP(+) channels in the underlying mechanisms. (c) 2006 Elsevier Ltd. All rights reserved.