Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist.
Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist.
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DOI：
10.1186/1744-8069-9-32
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发表时间：
2013-07-01
期刊：
影响因子：
3.3
通讯作者：
Zamponi GW
中科院分区：
文献类型：
--
作者：
Gadotti VM;You H;Petrov RR;Berger ND;Diaz P;Zamponi GW
大麻素受体和T型钙通道是治疗疼痛的潜在靶点。在这里，我们报告了一个新的混合大麻素/T型通道配体，NMP-181的设计，合成和镇痛性能。在放射性配体结合和体外GTPγ[35 S]功能测定中表征NMP-181对CB 1和CB 2受体的作用，并通过膜片钳分析NMP-181对瞬时表达的人Cav3.2 T型通道的阻断。在福尔马林和CFA小鼠疼痛模型中分析了经脊髓或全身递送的NMP-181的镇痛作用和体内作用机制。NMP-181抑制峰值CaV3.2电流，IC 50值在低微摩尔范围内，并作为CB 2激动剂。失活状态依赖性进一步增强了NMP-181的抑制作用。当在福尔马林试验的两个阶段中经脊髓或全身给药时，NMP-181产生剂量依赖性抗伤害效应。两个i.t.用NMP-181腹腔内处理小鼠可逆转CFA注射诱导的机械性痛觉过敏。NMP-181在CaV3.2敲除小鼠中未显示抗伤害作用。在福尔马林试验中鞘内递送的NMP-181的抗伤害感受作用被i. t.用AM-630（CB 2拮抗剂）治疗小鼠。相比之下，NMP-181诱导的抗伤害感受不受AM-281（CB 1拮抗剂）处理小鼠的影响。我们的工作表明，T型通道以及CB 2受体在NMP-181的抗伤害作用中发挥作用，并且还提供了一种通过新型混合T型/大麻素受体配体抑制慢性疼痛的新途径。
Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTPγ[35S] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak CaV3.2 currents with IC50 values in the low micromolar range and acted as a CB2 agonist. Inactivated state dependence further augmented the inhibitory action of NMP-181. NMP-181 produced a dose-dependent antinociceptive effect when administered either spinally or systemically in both phases of the formalin test. Both i.t. and i.p. treatment of mice with NMP-181 reversed the mechanical hyperalgesia induced by CFA injection. NMP-181 showed no antinocieptive effect in CaV3.2 null mice. The antinociceptive effect of intrathecally delivered NMP-181 in the formalin test was reversed by i.t. treatment of mice with AM-630 (CB2 antagonist). In contrast, the NMP-181-induced antinociception was not affected by treatment of mice with AM-281 (CB1 antagonist). Our work shows that both T-type channels as well as CB2 receptors play a role in the antinociceptive action of NMP-181, and also provides a novel avenue for suppressing chronic pain through novel mixed T-type/cannabinoid receptor ligands.
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影响因子：
5.5
作者：
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通讯作者：
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作者：
GERARD, CM;MOLLEREAU, C;PARMENTIER, M
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