title: The analgesic actions of centrally administered celecoxib are mediated by endogenous opioids.
abstract: 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.
authors.affiliation: 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.
authors.forename: Rafael Machado
authors.initials: RM
authors.lastname: Rezende
authors.forename: Webster Glayser Pimenta
authors.initials: WG
authors.lastname: Dos Reis
authors.forename: Igor Dimitri Gama
authors.initials: ID
authors.lastname: Duarte
authors.forename: Patrícia Paiva
authors.initials: PP
authors.lastname: Lima
authors.forename: Yeshwant S
authors.initials: YS
authors.lastname: Bakhle
authors.forename: Janetti Nogueira
authors.initials: JN
authors.lastname: de Francischi
mesh_terms: 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
chemical_list: 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