Preclinical Comparison of Mechanistically Different Antiseizure, Antinociceptive, and/or Antidepressant Drugs in a Battery of Rodent Models of Nociceptive and Neuropathic Pain

Abstract

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.

NYX-2925 Is a Novel N-Methyl-d-Aspartate Receptor Modulator that Induces Rapid and Long-Lasting Analgesia in Rat Models of Neuropathic Pain

“…This supports the specific target of NYX-2925 function to be within corticolimbic circuitry since the tail flick response is a spinally mediated phenomenon. Further support for this comes from reports that other compounds with analgesic effects in neuropathic pain conditions do not show effects in the tail flick test (Smith et al, 2017), which further reinforces the concept that neuropathic pain is distinct from nociceptive pain.…”

Antinociceptive and anti-inflammatory effects of 1,2-bis-(4 methoxyphenylselanyl) styrene in mice: involvement of the serotonergic system

“…Also, one remarkable characteristic about some antidepressant drugs is that their analgesic effect is already present shortly after the administration of the first dose. [37][38][39] An important finding of this study was that ondansetron when administered along with BMOSE inhibited the reduction in paw-licking response elicited by BMOSE, blocking the compound antinociceptive activity. This result shows that BMOSE activity is associated with the serotonergic pathway, more specifically, with 5-HT 3 receptors.…”

“…Therefore, pharmacological drugs that model the serotoninergic system, such as antidepressants, are widely used in the treatment of pain. Also, one remarkable characteristic about some antidepressant drugs is that their analgesic effect is already present shortly after the administration of the first dose …”

Modulating the Serotonin Receptor Spectrum of Pulicatin Natural Products

“…In identical assays performed in the same lab, antinociceptive compounds generally act at doses in the range of ~1 (i.e., morphine) to ~300 (i.e., aspirin) mg/kg. 28 …”