Berger N Daniel, Gadotti Vinicius M, Petrov Ravil R, Chapman Kevin, Diaz Philippe, Zamponi Gerald W
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
Mol Pain. 2014 Dec 6;10:77. doi: 10.1186/1744-8069-10-77.
T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund's Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury.
NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se, as evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV3.2 as a key target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo.
Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channel blockers.
已知T型钙通道和大麻素受体在慢性疼痛中发挥重要作用，使其成为有吸引力的治疗靶点。我们最近报道了一种新型T型通道抑制剂（NMP - 7）的设计、合成及镇痛特性，该抑制剂在体外对CB1和CB2受体也表现出混合激动剂活性。在此，我们分析了经全身给药（腹腔内（i.p.）或胃内（i.g.）途径）的NMP - 7对完全弗氏佐剂（CFA）诱导的炎性疼痛和坐骨神经损伤诱导的神经性疼痛中机械性超敏反应的镇痛作用。
通过i.p.或i.g.途径给药的NMP - 7在炎性和神经性疼痛小鼠模型中产生了剂量依赖性的机械性痛觉过敏抑制作用，在最高有效剂量下未改变旷场试验中的自发运动活性。通过检查爪肿胀和髓过氧化物酶活性评估，i.p.和i.g.治疗均未降低外周炎症本身。NMP - 7在CFA试验中产生的抗伤害感受在CaV3.2基因敲除小鼠中完全消除，证实CaV3.2是关键靶点。腹腔内给药的NMP - 7的镇痛作用不受CB1拮抗剂AM281预处理小鼠的影响，但被CB2拮抗剂AM630预处理显著减弱，表明CB2受体而非CB1受体参与了NMP - 7在体内的作用。
总体而言，我们的研究表明NMP - 7通过T型通道调节和CB2受体激活在持续性炎性和慢性神经性疼痛模型中介导了显著的镇痛作用。因此，本研究为通过混合CB配体/T型通道阻滞剂治疗慢性疼痛提供了一条新的治疗途径。
