Evidence for a central mechanism of action of S-(+)-ketoprofen.
It has been observed that some non-steroidal anti-inflammatory drugs (NSAIDs) may act through several mechanisms, in addition to central inhibition of prostaglandin synthesis. These other mechanisms include the L-arginine-nitric oxide (L-arginine-NO) pathway, as well as endogenous opiate and serotonergic mechanisms. Some of these mechanisms can explain the efficacy of NSAIDs in chronic pain conditions such as rheumatoid arthritis. The present study was designed to elucidate the involvement of the above pathways/mechanisms in the antinociceptive effect of S-(+)-ketoprofen at supraspinal and spinal levels. S-(+)-ketoprofen induced dose-dependent antinociception in the pain-induced functional impairment model in the rat. The antinociceptive effect of S-(+)-ketoprofen was not altered by i.t. or intracerebroventricula (i.c.v.) pre-treatment with L-arginine (29.6 microg/site) and L-nitro-arginine-monomethylester (L-NAME) (21.1 microg/site) and neither was the effect of S-(+)-ketoprofen modified by the opiate antagonist, naloxone (1 mg/kg, s.c.). In marked contrast, both i.c.v. administration of the 5-hydroxytryptamine (5-HT)(1)/5-HT(2)/5-HT(7) receptor antagonist, methiothepin (1.5 microg/site), and i.t. administration of the 5-HT(3)/5-HT(4) receptor antagonist, tropisetron (0.9 microg/site), significantly inhibited the S-(+)-ketoprofen-induced antinociceptive effect. These data suggest that the antinociceptive response to S-(+)-ketoprofen involves serotoninergic mechanisms via both supraspinal 5-HT(1)/5-HT(2)/5-HT(7) receptors and 5-HT(3) receptors located at spinal level. A role of the L-arginine-NO and opiate systems in S-(+)-ketoprofen-induced antinociception in the pain-induced functional impairment model in the rat model seems unlikely.
Díaz-Reval
María Irene
MI
Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio No. 965, Col. Villa San Sebastián, C.P. 28045 Colima, Col., Mexico. idiazre@cgic.ucol.mx
Ventura-Martínez
Rosa
R
Déciga-Campos
Myrna
M
Terrón
José A
JA
Cabré
Francesc
F
López-Muñoz
Francisco Javier
FJ
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007536:Isomerism; D007660:Ketoprofen / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology
D000700:Analgesics; D011985:Receptors, Serotonin; D007660:Ketoprofen