Antinociceptive effects of NCX-701 (nitro-paracetamol) in neuropathic rats: enhancement of antinociception by co-administration with gabapentin.
OBJECTIVE
Neuropathic pain is characterized by a poor response to classic analgesics. In the present study, we have assessed the antinociceptive activity of NCX-701 (nitro-paracetamol) in neuropathic rats, after systemic and intrathecal (i.t.) administration. In addition, we analysed the possible benefit of the combination of NCX-701 and gabapentin, a well-known potent analgesic, in the treatment of neuropathic pain.


METHODS
The antinociceptive effects of i.v. and i.t. NCX-701 and paracetamol were studied in spinal cord neuronal responses from neuropathic adult male Wistar rats, using the recording of single motor units technique. The effect of i.v. and i.t. NCX-701 in combination with i.v. gabapentin was studied by isobolographic analysis.


RESULTS
The experiments showed that NCX-701, but not paracetamol, dose-dependently reduced the nociceptive responses evoked by noxious mechanical and electrical stimulation, after i.v. (ID(50) 542 +/- 5 micromol kg(-1) for noxious mechanical stimulation) or i.t. (ID(50) 932 +/- 16 nmol kg(-1)) administration. The combined administration of i.v. or i.t. NCX-701 and i.v. gabapentin induced a more intense antinociceptive effect than any of the two drugs given alone. The isobolographic analysis showed a synergistic effect.


CONCLUSIONS
NCX-701 is an effective antinociceptive compound in situations of neuropathy-induced sensitization, with an action mainly located in the spinal cord. The combination of NCX-701 and gabapentin induces a synergistic enhancement of the depression of nociceptive responses evoked by natural noxious stimulation. The use of NCX-701 alone or in combination with gabapentin might open up new and promising perspectives in the treatment of neuropathic pain.
Curros-Criado
M Mar
MM
Departamento de Fisiología, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
Herrero
Juan F
JF
D000082:Acetaminophen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077206:Gabapentin; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009566:Nitrates / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D009566:Nitrates; D000082:Acetaminophen; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C478738:4-(nitroxy)butanoic acid 4-acetylaminophenyl ester