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.

Anticonvulsant Met-enkephalin analogues containing backbone spacers reveal alternative non-opioid signaling in the brain.

Prosthesis of non-critical parts of a polypeptide backbone is an attractive strategy to simplify bioactive peptides. This approach was applied to an opioid neuropeptide, Met-enkephalin, in which two adjacent Gly2-Gly3 residues were replaced with a series of non-peptidic backbone spacers varying in length and/or physicochemical properties. The backbone spacers did not affect the overall structural properties of the analogues, but they did dramatically reduce their affinities and agonist activities toward delta- and mu-opioid receptors. Molecular modeling suggested that the decrease of the affinity of Met-enkephalin to delta-opioid receptor could be accounted for by the loss of a single hydrogen bond. Remarkably, the analogues containing the most isostere spacers retained potent antinociceptive and anticonvulsant properties that were comparable to that of the endogenous peptide. This unexpected high in vivo potency could not be accounted for by an increase in metabolic stability. Moreover, the antiepileptic activity could not be reversed by opioid receptor antagonists. In summary, the results obtained with the analogues containing backbone spacers suggest a novel mechanism for seizure control in the brain that involves alternative non-opioid signaling.