RESUMEN
BACKGROUND/AIMS: In this study we analyzed the mechanisms underlying celecoxib-induced analgesia in a model of inflammatory pain in rats, using the intracerebroventricular (i.c.v.) administration of selective opioid and cannabinoid antagonists. METHODS AND RESULTS: Analgesic effects of celecoxib were prevented by selective µ-(ß-funaltrexamine) and δ-(naltrindole), but not κ-(nor-binaltorphimine) opioid antagonists, given i.c.v. 30 min before celecoxib. Similar pretreatment with AM 251, but not SR 144528, cannabinoid CB(1) and CB(2) receptor antagonists, respectively, prevented celecoxib-induced analgesia. The fatty acid amide hydrolase inhibitor, URB 597, also prevented celecoxib-induced analgesia. CONCLUSIONS: Our data provided further evidence for the involvement of endogenous opioids and revealed a new cannabinoid component of the mechanism(s) underlying celecoxib-induced analgesia.
Asunto(s)
Analgésicos/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/fisiología , Receptores Opioides delta/fisiología , Receptores Opioides mu/fisiología , Sulfonamidas/farmacología , Animales , Carragenina , Celecoxib , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/fisiopatología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidoresRESUMEN
BACKGROUND AND PURPOSE: The analgesics, paracetamol and dipyrone are weak inhibitors of the cyclooxygenase isoforms 1 or 2 (COX-1, COX-2) but more potent on COX-3. Both are also weak anti-inflammatory agents, relative to their analgesic and antipyretic activities. In a model of inflammatory pain mediated by prostaglandins, both compounds were analgesic. We have analysed this shared effect further in order to elucidate the underlying mechanisms. EXPERIMENTAL APPROACH: Inflammation was induced in one hind paw of rats by intraplantar injection of 250 microg lambda-carrageenan (CG) and the contralateral paw injected with saline. Nociceptive thresholds to mechanical stimulation were measured immediately before and for 6 h after, injection of CG. The analgesics were s.c. or locally (intraplantar) injected either 30 min before or 2 h after CG. In some groups, naltrexone was injected (s.c. or intraplantar), 1 h before CG. KEY RESULTS: Pretreatment with paracetamol or dipyrone (60-360 mg kg(-1)) reversed hyperalgesia induced by CG and increased nociceptive threshold in the inflamed paw above the basal level (hypoalgesia). Paracetamol, but not dipyrone, also raised nociceptive thresholds in the non-inflamed paw. Subcutaneous, but not local, administration of naltrexone, a specific opioid antagonist, reversed the hypoalgesia induced by paracetamol, but similar naltrexone treatment had no effect on dipyrone-induced analgesia. CONCLUSIONS AND IMPLICATIONS: Although both paracetamol and dipyrone are inhibitors of COX isoforms and thus of prostaglandin biosynthesis and were analgesic in our model, their analgesic actions were functionally and mechanistically different. Satisfactory mechanisms of action for these analgesics still remain to be established.
Asunto(s)
Acetaminofén/farmacología , Analgésicos no Narcóticos/farmacología , Dipirona/farmacología , Hiperalgesia/prevención & control , Inflamación/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Dolor/prevención & control , Acetaminofén/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Animales , Carragenina , Dipirona/administración & dosificación , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inflamación/inducido químicamente , Inflamación/complicaciones , Inflamación/metabolismo , Inflamación/fisiopatología , Inyecciones Intralesiones , Inyecciones Subcutáneas , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/antagonistas & inhibidores , Péptidos Opioides/metabolismo , Dolor/etiología , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Proyectos de Investigación , Factores de TiempoRESUMEN
OBJECTIVE AND DESIGN: To compare the production of hyperalgesic substances by cells from aged (A; 24-month) and juvenile (J; 2-month) rats. MATERIAL AND METHODS: 4 x 10(5) purified mononuclear cells from J and A were 2 h-stimulated (test) or not (control) by 250 microg lambda-carrageenan/well. Supernatants (0.1 ml) were intraplantarly (ipl) injected in rat paws and development of mechanical hyperalgesia, in grams, evaluated. Rat interleukin 2 (IL 2) and prostaglandin E2 (PGE2) were also assessed for hyperalgesia development. RESULTS: Test supernatants from A compared with J induced significantly less hyperalgesia (-56 +/- 8.1 and -88.4 +/- 4.6 g, respectively, p < 0.05, ANOVA t test). Local injection of a specific, but not a control, antiserum against IL 2 significantly blocked both pure IL 2- and stimulated supernatants-derived hyperalgesia. In contrast to PGE-like materials, IL 2 content in supernatants was compatible with hyperalgesia development. CONCLUSIONS: Hyperalgesia induced by test supernatants was significantly less intense when derived from aged animals. IL 2 may have accounted for such hyperalgesia.