Preclinical Comparison of Mechanistically Different Antiseizure, Antinociceptive, and/or Antidepressant Drugs in a Battery of Rodent Models of Nociceptive and Neuropathic Pain.
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.
['Smith|Misty D|MD|', 'Woodhead|Jose H|JH|', 'Handy|Laura J|LJ|', 'Pruess|Timothy H|TH|', 'Vanegas|Fabiola|F|', 'Grussendorf|Erin|E|', 'Grussendorf|Joel|J|', 'White|Karen|K|', 'Bulaj|Karolina K|KK|', 'Krumin|Reisa K|RK|', 'Hunt|Megan|M|', 'Wilcox|Karen S|KS|']
D000700:Analgesics D000818:Animals D000927:Anticonvulsants D000928:Antidepressive Agents D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004353:Drug Evaluation, Preclinical D008297:Male D051379:Mice D009437:Neuralgia D009557:Nipecotic Acids D010147:Pain Measurement D051381:Rats D017207:Rats, Sprague-Dawley D012377:Rodentia D000078308:Tiagabine
Pain models Formalin Writhing Tail flick Partial sciatic nerve ligation Antiseizure drugs