European journal of pharmacology
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Effects of different doses of aspirin, compared to equimolar doses of nitric oxide (NO)-donating aspirin (NCX 4016), and of a single dose of paracetamol, compared to an equimolar dose of NO-donating paracetamol (NCX 701) were investigated in acute zymosan-induced air pouch inflammation in rats. Treatments were administered by orogastric route, and interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) levels in the exudates were analysed 4 h after zymosan injection by enzyme immunoassay (EIA). Aspirin, at 10, 30 and 100 mg/kg doses, increased IL-1beta levels in exudates, however, only the highest dose lead to a significant increase when compared to control, whereas a significant increase in TNF-alpha level was observed at all doses tested. ⋯ Paracetamol and NO-paracetamol did not cause any change in the number of polymorphonuclear leukocytes in exudate. These results indicated that aspirin and NCX 4016 possessed different effects on cytokine production or release, despite the fact that both drugs inhibited the synthesis of PGE(2) in a similar way. Unlike paracetamol, which increased exudate TNF-alpha level, NCX 701 had no effect on TNF-alpha level in the exudates.
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In skeletal muscle sarcoplasmic reticulum vesicles, 3,5-di-t-butyl catechol (DTCAT) promotes the release of Ca(2+) through the activation of ryanodine receptor Ca(2+) channels. DTCAT mechanical and electrophysiological effects have now been investigated in rat aorta rings and single tail artery myocytes. Rat aorta rings incubated with either 30 microM ryanodine or 100 microM DTCAT developed tension, which averaged 36% and 7%, respectively, of that induced by phenylephrine. ⋯ DTCAT (>100 microM) was also able to antagonise the contractions induced by phorbol 12-myristate, 13-acetate. In conclusion, this is the first demonstration that DTCAT inhibits vascular smooth muscle voltage-operated Ca(2+) channels and promotes the release of endothelial nitric oxide. Ryanodine receptor Ca(2+) channels activation or the impairment of the contractile apparatus by DTCAT seem to play a secondary role in its vascular activity.
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Earlier, we reported that morphine-nimodipine combination produces significantly higher antinociception after intrathecal but not after systemic administration in mice. Different doses of morphine and nimodipine (5 microg of morphine, 5 microg of nimodipine, 5 microg each of morphine and nimodipine, 10 microg of morphine, 10 microg of nimodipine, 10 microg morphine with 5 microg nimodipine and 5 microg of morphine with 10 microg of nimodipine) were now injected intrathecally in Wistar rats to further characterise this antinociceptive effect. The acute antinociceptive effect was measured by the tail-flick test between 15 min to 7 h. ⋯ Naloxone (5 mg/kg) could reverse this antinociceptive effect of morphine-nimodipine combination though it failed to reverse nimodipine (5 microg)-mediated antinociception at 15 min. Increasing the dose of either morphine or nimodipine to 10 mug did not increase antinociception except between 6:30-7:00 h. No obvious side effect was noted after administration of either morphine or nimodipine or both.
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Peroxisome proliferator activated receptors (PPAR) are ligand-regulated transcription factors that control the expression of many genes. The antiinflammatory activity of fibrates, PPARalpha agonists, and thiazolidinediones, PPARgamma agonists, has been demonstrated in many in vitro and a few in vivo studies. In the present study, we evaluated the effect of acute (100 or 300 mg/kg, p.o.) or prolonged (100 or 300 mg/kg day, 7 days, p.o.) treatment with fenofibrate and acute treatment with pioglitazone (doses ranging from 1 to 50 mg/kg, i.p.), PPARalpha and PPARgamma agonists, respectively, on experimental models of nociception and edema, in order to expand the knowledge of their potential antiinflammatory activities. ⋯ Fenofibrate did not inhibit mechanical allodynia or paw edema induced by phorbol-12,13-didecanoate (PDD), a protein kinase C activator, in rats. Pioglitazone inhibited paw edema, but not mechanical allodynia, induced by PDD. The results represent the first demonstration of the antinociceptive and antiedematogenic activities of fenofibrate and pioglitazone and give further support to the potential use of PPAR agonists in the treatment of different inflammatory diseases.
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Recent research has shown that microglial cells which are strongly activated in neuropathy can influence development of allodynia and hyperalgesia. Here we demonstrated that preemptive and repeated i.p., administration (16 h and 1 h before injury and then after nerve ligation twice daily for 7 days) of minocycline (15; 30; 50 mg/kg), a potent inhibitor of microglial activation, significantly attenuated the allodynia (von Frey test) and hyperalgesia (cold plate test) measured on day 3, 5, 7 after chronic constriction injury (CCI) in rats. Moreover, the 40% improvement of motor function was observed. ⋯ Antiallodynic and antihyperalgesic effect of morphine (10 mg/kg; i.p.) was significantly potentiated in groups preemptively and repeatedly injected with minocycline (von Frey test, 18 g versus 22 g; cold plate test, 13 s versus 20 s in rats and 1.2 g versus 2.2 g; 7.5 s versus 10 s in mice; respectively) or pentoxifylline (1.3 g versus 3 g; 7.6 s versus 15 s in mice; respectively). Antiallodynic and antihyperalgesic effect of morphine (30 microg; i.t.) given by lumbar puncture in mice was also significantly potentiated in minocycline-treated group (1.2 g versus 2.2 g; 7.5 s versus 11 s; respectively). These findings indicate that preemptive and repeated administration of glial inhibitors suppresses development of allodynia and hyperalgesia and potentiates effects of morphine in rat and mouse models of neuropathic pain.