Celecoxib induces tolerance in a model of peripheral inflammatory pain in rats.
Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). Like most NSAIDs, celecoxib exhibits analgesic effects in models of inflammatory pain but these appear to be dependent on endogenous opioid release. Therefore, this study has assessed the ability of celecoxib to induce tolerance in rats, comparable to that induced by morphine. Rats were injected subcutaneously (s.c.) twice daily with divided doses of celecoxib, morphine or indomethacin. Inflammation was induced in one hind paw of rats by injecting prostaglandin E(2) (PGE(2); 200 ng) 30 min after drug administration, on days 1, 3, 5 and 6 or 7. Nociceptive thresholds to mechanical stimulation were measured 3 h after PGE(2) injection, on the same days. On days 6 or 7, analgesic effects of the full doses of test drugs were assessed. Celecoxib-induced tolerance, as did morphine, an effect not shown by another NSAID, indomethacin. Cross-tolerance between celecoxib and morphine was observed as they did not induce analgesia when animals were chronically treated with morphine or celecoxib, respectively. In addition, tolerance to celecoxib's analgesic effects persisted for at least two days after the end of the chronic treatment with celecoxib. Naltrexone prevented induction of tolerance to morphine or celecoxib. The present results strengthen the possibility that celecoxib has also mechanisms of analgesia unrelated to COX inhibition but dependent on endogenous opioid release. Our results also imply the existence of a new class of analgesics without the deleterious effects of COX inhibitors.
Rezende
Rafael Machado
RM
Federal University of Minas Gerais, Institute of Biological Sciences, Department of Pharmacology, Laboratory of Inflammation and Pain, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, Brazil.
Paiva-Lima
Patrícia
P
Dos Reis
Webster Glayser Pimenta
WG
Camêlo
Vinícius Mesquita
VM
Bakhle
Y S
YS
de Francischi
Janetti Nogueira
JN
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000068579:Celecoxib; D015232:Dinoprostone / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000700:Analgesics; D011720:Pyrazoles; D013449:Sulfonamides; D009020:Morphine; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin