RESUMO
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.
Assuntos
Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Análise de Variância , Animais , Celecoxib , Dinoprostona/farmacologia , Hiperalgesia/induzido quimicamente , Indometacina/farmacologia , Indometacina/uso terapêutico , Inflamação/induzido quimicamente , Morfina/farmacologia , Morfina/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Estimulação Física , Pirazóis/farmacologia , Ratos , Sulfonamidas/farmacologiaRESUMO
In a model of peripherally induced inflammatory pain in rats, selective inhibitors of cyclooxygenase (COX)-2 raised nociceptive thresholds above basal values, an effect referred to as "hypoalgesia". However other, non-selective, inhibitors of COX (indomethacin, piroxicam) or a selective inhibitor of COX-1 did not induce hypoalgesia in this model, implying that COX inhibition was not causally related to the hypoalgesic effect. Here, we have assessed whether other COX-2 inhibitors or other sulphonamides, apart from celecoxib could exhibit hypoalgesia in our model of inflammatory pain. Inflammation was induced in one hind paw of rats by intraplantar injection of carrageenan (250 µg). Nociceptive thresholds to mechanical stimulation were measured in the inflamed and contralateral paws for 6 h after carrageenan. Three sulphonamides, celecoxib itself, furosemide (a loop diuretic), acetazolamide (a carbonic anhydrase inhibitor), or a selective COX-2 inhibitor lacking the sulphonamide group, lumiracoxib, were injected s.c., 30 min before the pro-inflammatory stimulus. Naltrexone, a non-selective opioid antagonist was also administered s.c., 30 min before test drugs. Furosemide and acetazolamide dose-dependently induced hypoalgesia in the inflamed paw, as did celecoxib. However, lumiracoxib only produced anti-hyperalgesia. Pre-treatment with naltrexone completely prevented the hypoalgesia induced by the sulphonamides, but only partially prevented the anti-hyperalgesic effect of lumiracoxib. Taken together, our results suggest that the sulphonamide group in the structure of celecoxib is more critical for the development of hypoalgesia in our model than its ability to inhibit COX-2. Further, other sulphonamides lacking significant COX inhibition were also able to exhibit hypoalgesic effects, mediated by the endogenous opioid system.
Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dor/tratamento farmacológico , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Acetazolamida/administração & dosagem , Acetazolamida/química , Acetazolamida/farmacologia , Animais , Celecoxib , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Diclofenaco/administração & dosagem , Diclofenaco/análogos & derivados , Diclofenaco/química , Diclofenaco/farmacologia , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Naltrexona/administração & dosagem , Naltrexona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Pirazóis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagemRESUMO
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.
Assuntos
Analgésicos Opioides/metabolismo , Anti-Inflamatórios não Esteroides/administração & dosagem , Carragenina/efeitos adversos , Dor/tratamento farmacológico , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Analgésicos Opioides/administração & dosagem , Análise de Variância , Animais , Celecoxib , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Esquema de Medicação , Interações Medicamentosas , Inibidores Enzimáticos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/complicações , Injeções Intraventriculares/métodos , Leucina/administração & dosagem , Leucina/análogos & derivados , Masculino , Morfina/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Dor/etiologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ratos , Tempo de Reação/efeitos dos fármacos , Fatores de TempoRESUMO
To investigate whether selective COX 2 inhibitors (celecoxib, rofecoxib) would play a role in a model of leukocyte migration in rats. Bacterial endotoxin (Escherichia coli LPS) was intraperitoneally injected at time zero in rats that were previously treated with unspecific and selective cyclooxygenase inhibitors. LPS induced a dose and time-dependent increase in leukocyte number, which was predominantly related to the presence of PMN neutrophils. Only rats treated with selective COX 2 inhibitors and indomethacin showed a significant reduction in leukocyte numbers following LPS administration. Prostaglandins E(2) and F(2alpha) were injected into the peritoneum and the chemoatractant effect was studied. Only PGF(2alpha) was able to induce neutrophil increase following injection. Intraperitoneal reposition of PGF(2alpha) restored the abrogated leukocyte response to LPS, shown by rats pretreated with rofecoxib. It can be concluded that COX 2, through PGF(2alpha) release, is the isoform responsible for neutrophil recruitment in the rat model of LPS-induced inflammation.