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Pretreatment with captopril, a kininase II inhibitor, at 10 mg/kg i.p. or s.c., significantly increased the writhing response induced by a minimum effective dose (0.75 mg/kg i.p.) of phenylbenzoquinone (PBQ), by 91-148%. 1,10-Phenanthroline, a carboxypeptidase B inhibitor (2 mg/kg i.p.), in combination with captopril enhanced the algesic effect of PBQ by 309-360%. Captopril also doubled the number of writhes induced by a minimum effective dose of BK (5 micrograms/kg i.p.) in PGE2-pretreated mice. The writhing responses induced by higher doses of PBQ or BK were not affected by these inhibitors. The hyperalgesic effect of BK (1 micrograms) injected into the hindpaw of rats was significantly increased and prolonged by coinjection of captopril (30 micrograms) and 1,10-phenanthroline (30 micrograms) and was prevented by carboxypeptidase B (1 mg). These data indicate that BK plays a role in pain in these models, a role which appears of greatest relevance at threshold algesic stimulation.

The effectiveness of 5-lipoxygenase (LO) and dual LO/cyclooxygenase (CO) inhibitors when administered by the topical or oral routes was significantly decreased in corticosterone depleted (adrenalectomized, Adx) mice as compared to sham mice in the mouse arachidonic acid (AA) induced ear edema model. In contrast, rat carrageenan paw edema was inhibited similarly in sham and Adx animals by 5-LO and dual 5-LO/CO inhibitors. Supplementation of cortisol levels (100 micrograms/dl) in human whole blood for 2 hr increased the observed inhibition of LTB4 biosynthesis by A-64077, WY-50,295 tromethamine and naproxen while having no effect on thromboxane B2 (TXB2) biosynthesis. Thus, corticosteroids may have a permissive effect by modulating 5-LO inhibitor effects on mouse AA induced ear edema and human blood leukocytes.

Melittin (MLT) (10 micrograms/paw) and D49 (0.4 micrograms/paw) were injected into the hind paw of male CD-1 mice and elicited 70-80% of maximal paw edema responses at 60 and 30 min after injection, respectively. D49 paw edema was significantly inhibited by anti-histamine/serotonin agents, a PAF antagonist, a PLA2 inhibitor, and some but not all 5-LO and CO inhibitors, indicating that this edema is produced by several classes of inflammatory mediators with mast cell degranulation apparently playing a major role. In contrast, MLT paw edema was not inhibited effectively using the same pharmacological agents except theophylline, suggesting it was elicited via a different sequence of inflammatory events. In summary, D49 and MLT paw edema models were found to be ineffective models to identify experimental PLA2 compounds in our laboratory.

Paw edema was produced in CD-1 mice by the injection of 0.3 micrograms of snake venom PLA2 (A.p. piscivorus D-49) into the hind paw. Edema peaked at 10 min, remained elevated until 60 min, and then declined slowly. The PLA2 inhibitors, luffariellolide and aristolochic acid, reduced the edema but only when coinjected with the PLA2. The histamine/serotonin antagonists were the most effective drug class against PLA2-induced paw edema. The PAF antagonists, CV-6202 (iv) and kadsurenone (coinjected) reduced the PLA2-induced edema, whereas high doses of the corticosteroids, dexamethasone and hydrocortisone, were also effective. NSAIDs only partially inhibited the paw edema. The LO/CO inhibitors yielded varying activities, with only BW755C and NDGA inhibiting the edema. These results suggest that PLA2 induces paw edema in the mouse via the action of several classes of inflammatory mediators.

The intraperitoneal injection of 1 mg/kg PGE2 (which by itself was inactive) enhanced the writhing response induced by a subnociceptive dose of bradykinin (BK, 0.5 mg/kg ip) in male mice. The BK1 agonist, DesArg9-BK and the BK1 antagonist DesArg9-Leu8-BK did not affect writhing. The BK2 agonists, Lys-BK and Tyr-BK, like BK, induced writhing in the PGE2-treated mice. On the other hand, the DPhe7-analogs of BK, which antagonize BK at the BK2 subtype of receptors, potently inhibited the writhing response induced by BK. The writhing was also inhibited by morphine, but in contrast, non-steroidal antiinflammatory drugs (NSAIDs) only weakly inhibited the writhing response in this assay, suggesting that the nociceptive effect of BK was not significantly dependent upon the biosynthesis of PGE2. These results suggest that the algesic effect of BK in this mouse model is mediated via a BK2 receptor subtype.