The analgesic actions of centrally administered celecoxib are mediated by endogenous opioids.
Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2) and blocks prostaglandin (PG) biosynthesis associated with inflammatory conditions. In a model of peripherally induced inflammatory pain in rats, celecoxib, given systemically, induced a state of hypoalgesia where the nociceptive threshold was raised above basal values, an effect not observed after treatment with non-selective inhibitors of COX (indomethacin, piroxicam). Here, we have assessed the possibility that these atypical effects of celecoxib could be mediated by action at a site in the CNS. Inflammation and hyperalgesia were induced in one hind paw of rats by intraplantar injection of carrageenan (250microg). Nociceptive thresholds to mechanical stimulation were measured in the inflammed and contralateral paws for 6h after carrageenan injection. Celecoxib, SC236 (selective COX-2 inhibitors), indomethacin (non-selective COX inhibitor), SC560 (selective COX-1 inhibitor) or morphine were given by i.c.v. injection, 30 min before carrageenan. Celecoxib, SC236 or morphine-induced hypoalgesia whereas, after indomethacin or SC 560, the nociceptive threshold only returned to basal values. Naltrexone, also given i.c.v., reversed the hypoalgesia after celecoxib or morphine. Bestatin, an inhibitor of metabolism of endogenous opioid peptides, given i.c.v., potentiated the analgesic effects of a low dose of celecoxib. Taken together, these data indicate that celecoxib could act centrally after systemic administration to produce its characteristic profile of analgesia in this model of peripheral inflammatory pain. Moreover, this atypical analgesia appeared to be mediated by endogenous opioids rather than by inhibition of PG biosynthesis.
Rezende
Rafael Machado
RM
Laboratory of Inflammation and Pain, Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, Brazil.
Dos Reis
Webster Glayser Pimenta
WG
Duarte
Igor Dimitri Gama
ID
Lima
Patrícia Paiva
PP
Bakhle
Yeshwant S
YS
de Francischi
Janetti Nogueira
JN
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D002351:Carrageenan / Q000009:adverse effects*; D000068579:Celecoxib; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007155:Immunologic Factors / Q000008:administration & dosage; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D007276:Injections, Intraventricular / Q000379:methods; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives; D008297:Male; D009020:Morphine / Q000008:administration & dosage; D009271:Naltrexone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage*; D013997:Time Factors
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D009292:Narcotic Antagonists; D011720:Pyrazoles; D013449:Sulfonamides; D009271:Naltrexone; D009020:Morphine; D002351:Carrageenan; D007930:Leucine; C012211:ubenimex; D000068579:Celecoxib