Smith Misty D, Woodhead Jose H, Handy Laura J, Pruess Timothy H, Vanegas Fabiola, Grussendorf Erin, Grussendorf Joel, White Karen, Bulaj Karolina K, Krumin Reisa K, Hunt Megan, Wilcox Karen S
Epilepsy Therapy Screening Program Contract Site, Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, UT, 84108, USA.
School of Dentistry, University of Utah, Salt Lake City, 84112, USA.
Neurochem Res. 2017 Jul;42(7):1995-2010. doi: 10.1007/s11064-017-2286-9. Epub 2017 May 15.
The series of experiments herein evaluated prototype drugs representing different mechanisms of antiseizure, antinociceptive or antidepressant action in a battery of preclinical pain models in adult male CF#1 mice (formalin, writhing, and tail flick) and Sprague Dawley rats partial sciatic nerve ligation (PSNL). In the formalin assay, phenytoin (PHT, 6 mg/kg), sodium valproate (VPA, 300 mg/kg), amitriptyline (AMI, 7.5 and 15 mg/kg), gabapentin (GBP, 30 and 70 mg/kg), tiagabine (TGB, 5 and 15 mg/kg), and acetominophen (APAP, 250 and 500 mg/kg) reduced both phases of the formalin response to ≤ 25% of vehicle-treated mice. In the acetic acid induced writhing assay, VPA (300 mg/kg), ethosuximide (ETX, 300 mg/kg), morphine (MOR, 5 & 10 mg/kg), GBP (10, 30, and 60 mg/kg), TGB (15 mg/kg), levetiracetam (LEV, 300 mg/kg), felbamate (FBM, 80 mg/kg) and APAP (250 mg/kg) reduced writhing to ≤ 25% of vehicle-treated mice. In the tail flick test, MOR (1.25-5 mg/kg), AMI (15 mg/kg) and TGB (5 mg/kg) demonstrated significant antinociceptive effects. Finally, carbamazepine (CBZ, 20 and 50 mg/kg), VPA, MOR (2 and 4 mg/kg), AMI (12 mg/kg), TPM (100 mg/kg), lamotrigine (LTG, 40 mg/kg), GBP (60 mg/kg), TGB (15 mg/kg), FBM (35 mg/kg), and APAP (250 mg/kg) were effective in the PSNL model. Thus, TGB was the only prototype compound with significant analgesic effects in each of the four models, while AMI, GBP, APAP, and MOR each improved three of the four pain phenotypes. This study highlights the importance evaluating novel targets in a variety of pain phenotypes.
本系列实验评估了一系列原型药物，这些药物在成年雄性CF#1小鼠（福尔马林、扭体和甩尾）的一系列临床前疼痛模型以及Sprague Dawley大鼠坐骨神经部分结扎（PSNL）模型中代表了不同的抗癫痫、抗伤害感受或抗抑郁作用机制。在福尔马林试验中，苯妥英（PHT，6mg/kg）、丙戊酸钠（VPA，300mg/kg）、阿米替林（AMI，7.5和15mg/kg）、加巴喷丁（GBP，30和70mg/kg）、噻加宾（TGB，5和15mg/kg）以及对乙酰氨基酚（APAP，250和500mg/kg）将福尔马林反应的两个阶段均降低至≤溶媒处理小鼠的25%。在醋酸诱导的扭体试验中，VPA（300mg/kg）、乙琥胺（ETX，300mg/kg）、吗啡（MOR，5和10mg/kg）、GBP（10、30和60mg/kg）、TGB（15mg/kg）、左乙拉西坦（LEV，300mg/kg）、非氨酯（FBM，80mg/kg）和APAP（250mg/kg）将扭体次数降低至≤溶媒处理小鼠的25%。在甩尾试验中，MOR（1.25 - 5mg/kg）、AMI（15mg/kg）和TGB（5mg/kg）表现出显著的抗伤害感受作用。最后，卡马西平（CBZ，20和50mg/kg）、VPA、MOR（2和4mg/kg）、AMI（12mg/kg）、托吡酯（TPM，100mg/kg）、拉莫三嗪（LTG，40mg/kg）、GBP（60mg/kg）、TGB（15mg/kg）、FBM（35mg/kg）和APAP（250mg/kg）在PSNL模型中有效。因此，TGB是唯一在四个模型中均具有显著镇痛作用的原型化合物，而AMI、GBP、APAP和MOR各自改善了四种疼痛表型中的三种。本研究强调了在多种疼痛表型中评估新靶点的重要性。
