Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea-pig: importance of the booster injection.

1. BN 52021, an antagonist of platelet activating factor (PAF), was inactive against bronchoconstriction in guinea-pigs sensitized with low amounts of ovalbumin (OA) injected twice, at a 14 day interval and challenged i.v. 7 days later. 2. Serum IgG titers increased for 7 weeks after the booster injection at day 14 and returned to low levels at day 96. 3. Administered by the intratracheal (i.t.) route at 1 mg, BN 52021 failed to inhibit bronchoconstriction induced by the i.t. administration of OA to guinea-pigs tested 7, 28, 56 and 84 days after the booster injection, even when the titers of circulating IgG had declined with time. BN 52021 was also inactive against bronchoconstriction in guinea-pigs boosted at day 98 and tested 7 days later and against contractions and thromboxane (Tx) B2 and histamine release induced by OA-challenged parenchymal lung strips from the boosted guinea-pigs. 4. Sensitized unboosted guinea-pigs displayed reduced IgG serum titers. Used 21 or 70 days after the sensitizing injection, they did develop bronchoconstriction upon the i.t. instillation of OA, which was blocked by BN 52021. The latter also inhibited OA-induced contractions of lung parenchymal strips from these unboosted guinea-pigs. 5. When boosted and non-boosted guinea-pigs received OA i.t. and bronchoalveolar lavage fluid was collected 10 min later, the number of eosinophils increased markedly in boosted, but not in non-boosted guinea-pigs. 6. The booster injection of antigen thus modifies the response of the lung and PAF appears to be relevant for antigen-induced bronchoconstriction in unboosted animals, but loses its major role following the booster injection.     

Reproducible biphasic cutaneous edema induced by topical and repeated application of antigen in sensitized mice

An allergic dermatitis model was developed by repeated sensitization and challenge with antigen (ovalbumin, OA) over 7 months in mice. ddY mice were sensitized by i.p. injection of OA adsorbed on Al(OH)3 (1 microg OA/2 mg Al(OH)3/animal) once every 3 weeks. Antigen challenge was conducted by injection of OA solution (0.1, 1 and 10 microg/site) into the skin of the hind paw instep 10 d after the respective sensitizations. At the 1st challenge, all the 3 groups showed an immediate edematous response with the peak at 30 min or 1 h after the challenge. The group challenged with the highest dose (10 microg/site) of the antigen developed a clear late-phase edema, which was observed at the 2nd challenge, increasing until the 3rd challenge, reaching a plateau at further challenges. On the other hand, such late phase edema scarcely developed in the group challenged with the lowest dose (0.1 microg/site) of the antigen. The amount of circulating specific IgE antibody increased following repeated sensitizations and challenges in all groups, but there were no significant differences in the levels among them. Mepyramine suppressed the early edema by approximately 50%, yet the late phase edema was unaffected. In conclusion, using Al(OH)3+antigen for sensitization and an appropriate amount of antigen for challenge, reproducible biphasic edematous responses were observed long-term without desensitization. This model may be classified as an acute allergic dermatitis and can be useful for quantitatively evaluating the effects of anti-allergic drugs.     

Anti-allergic effects of nilotinib on mast cell-mediated anaphylaxis like reactions

Nilotinib is a new orally bioavailable potent tyrosine kinase inhibitor that is used for the treatment of BCR-ABL-positive chronic myelogenous leukemia. However, its effect on mast cell-mediated anaphylactic reaction is still not known. The present study aimed to investigate the effect of nilotinib on the anaphylactic allergic reaction and study its possible mechanism(s) of action. Nilotinib administration prevented systemic anaphylaxis in mice, mediated by compound 48/80, in a dose- and time-dependent manner. Also, nilotinib significantly inhibited (P<0.05) allergic paw edema in rats. Furthermore, nilotinib significantly decreased (P<0.05) the IgE-mediated passive cutaneous anaphylaxis in a dose dependent manner. In addition, nilotinib dose-dependently reduced histamine release from the rat peritoneal mast cells activated either by compound 48/80 or by ovalbumin. Moreover, nilotinib attenuated the secretion of pro-inflammatory cytokine, tumor necrosis factor (TNF)-α expression in the rat peritoneal mast cells. These findings provide evidence that nilotinib inhibits mast cell-derived immediate-type allergic reactions and so it could be a candidate as an anti-allergic agent.     

Neutralization of the oedematogenic activity of Bothrops jararaca venom on the mouse paw by an antibothropic fraction isolated from opossum (Didelphis marsupialis) serum.

The pharmacological modulation of mice paw oedema produced by Bothrops jararaca venom (BJV) has been studied. Intraplantar injection of BJV (1-30 micrograms/paw) produced a dose- and time-related oedema, which was maximal 30 min after injection, reduced gradually thereafter and disappeared over 48 h. BJV heated at 100 degrees C for 5 or 15 min blocked local hemorrhage and caused partial inhibition of its oedematogenic activity. The BJV oedema was not inhibited by the anti-histamine meclizine, the inhibitor of histamine and serotonin, cyproheptadine, PAF-acether antagonist WEB 2170 or by the anti-leukotrienes C4/D4, LY 171883. Dexamethasone, aspirin, indomethacin, and the dual cyclooxygenase and lipoxygenase inhibitor BW 755C inhibited BJV-induced oedema indicating that arachidonic acid metabolism products via the cyclooxygenase pathway participate in its genesis and/or maintenance. The antibothropic fraction (ABF) (25-200 micrograms/paw) isolated from Didelphis marsupialis serum neutralized the oedema induced by the venom with and without heating, the hemorrhage induced by BJV and partially blocked the oedema induced by bradykinin and by cellulose sulphate. The oedema produced by histamine, serotonin, PAF-acether or leukotriene C4 was not inhibited.     

The hind paw edema produced by staphylococcal enterotoxin B in female mice is modulated by sex hormones.

This paper describes the involvement of sex hormones in the edematogenic response produced by staphylococcal enterotoxin B (SEB) in the mouse hindpaw. Both the paw weight variation and the protein exudate produced by the intraplantar administration of SEB (12.5 micrograms/paw) to intact, randomly cycling female (IRCF) mice were significantly attenuated when the animals were ovariectomized (OVX). The attenuation of SEB-induced paw swelling produced by OVX was not reversed by estradiol (OE2) reposition. Thus, 4 h after the injection of SEB the increase in paw weight in OVX-mice treated with OE2 (10 micrograms/kg in corn oil) was 15.0 +/- 0.9 mg, while the exudation corresponded to 2.1 +/- 0.3 micrograms of Evans blue dye/g of tissue. Neither of these values differed significantly from those obtained 4 h after the intraplantar injection of SEB (12.5 micrograms/paw) in non-treated OVX-mice (paw swelling, 14.0 +/- 0.8 mg; dye exudation, 2.0 +/- 0.3 micrograms/g, N = 6). Pretreating IRCF mice once a day for three days with human chorionic gonadotrophin (40 IU/kg, i.m.) reduced the paw edema produced by the toxin, thus indicating an involvement of gonadotrophins in this event. A pronounced decrease in paw weight variation (about 45%) and dye exudation (61%) was detected when IRCF mice were previously treated every 72 h with three injections of OE2 (10 micrograms/kg in corn oil, i.m.). Similar situations were also seen when the animals were pretreated at 72 h intervals with three injections of testosterone (10 mg/kg in corn oil, i.m.). We conclude that the paw edema induced by SEB in female mice is hormonally regulated. Our results also indicate that the HPA-immune axis is involved in this phenomenon.     

Pharmacologic modulation of D-49 phospholipase A2-induced paw edema in the mouse

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.     

Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.     

Anti-allergic activity of 7-acetyl-5-oxo-5H-[1] benzopyrano (2,3-b] pyridine (Y-9000) (author's transl)]

The IgE mediated reactions such as 48 hr homologous passive cutaneous anaphylaxis (PCA) and active anaphylactic bronchoconstriction in rats were inhibited in a dose dependent manner by treatment with 7-acetyl-5-oxo-5H-[1]benzopyranol[2,3-b] pyridine (Y-9000) and disodium cromoglycate (DSCG) given intraperitoneally. The inhibitory activity of Y-9000 was to the same extent as that seen with DSCG. The IgE mediated reactions were also inhibited by oral treatment with Y-9000 but not with DSCG. In addition, the treatment with Y-9000 resulted in inhibition of IgG mediated reaction such as anaphylactic asthma in the passively sensitized guinea pigs and 4 hr heterologous PCA in rats. However, DSCG failed to prevent these reactions. Y-9000 also inhibited the active systemic anaphylaxis of the mouse and non-immunological reactions in rats such as histamine release after an intraperitoneal injection of dextran, anaphylactoid reaction and paw edema induced by the dextran, egg white or carrageenin. This agent had a stimulating effect on the adrenals, and showed glucocorticoid like activity, but bronchodilator and antagonistic activities on chemical mediators were nil. These results suggest that the anti-allergic activities of Y-9000 are elicited by inhibiting the release of allergic mediators in a manner similar to DSCG, and are partially mediated by stressor activity.     

风热汤的抗过敏、抗炎和止痒作用研究

目的探讨风热汤对大鼠被动皮肤过敏反应的影响及其抗炎、止痒作用。方法制备大鼠被动皮肤过敏反应模型,观察风热汤的抗过敏作用。采用炎症模型,观察给药后对二甲苯致小鼠耳廓肿胀和角叉菜胶致大鼠足趾肿胀的影响。采用瘙痒模型,观察给药后对葡聚糖-40致小鼠瘙痒和磷酸组胺致豚鼠瘙痒的影响。结果风热汤对血清抗原有抗过敏作用,对二甲苯所致小鼠耳廓肿胀和角叉菜胶所致的大鼠足趾肿胀有显著抗炎作用,能延长葡聚糖-40所致的小鼠瘙痒的潜伏期和减少瘙痒次数,对磷酸组胺致痒有止痒作用。结论风热汤具有抗过敏及抗炎、止痒的作用。     

Anti-edema effects of some H1-receptor antagonists]

Experiments carried out with mice of CFLP strain have shown that antihistaminics (chloropyramine, cyproheptadine and dimethindene maleate) significantly inhibit the extents of ear oedema induced by croton oil, dithranol or capsaicin. In rats of Wistar strain, oedema was induced in the hind paw by the subplantar injection of carrageenin, and simultaneously by the application of croton oil to the inner surface on the ear. Preliminary antihistamine treatment inhibited the development of both types of oedema, to statistically significant extent.     

Effects of terbutaline on NGF formation in allergic inflammation of the rat

1. The aim of this study was to determine the effects of the beta adrenergic agonist terbutaline on NGF increase caused by allergic inflammation in rats. 2. Intraplantar antigen injection in sensitized rats increased paw volume and stimulated NGF biosynthesis in the skin of the injected paw as determined 3 and 6 h after injection. Treatment of rats with terbutaline (0.1 - 0.3 mg kg(-1), s.c.) had no significant effect on the NGF concentration in non-inflamed skin, but reduced oedema, and at 0.3 mg kg(-1) also NGF mRNA and immunoreactive NGF in the skin of the inflamed paw in a propranolol-reversible manner. In carrageenan-induced inflammation, terbutaline did not significantly reduce the inflammation-induced increase of NGF in paw skin. 3. Exposure of sensitized rats to aerosolized antigen (twice, 24 h interval) increased protein content, eosinophil leukocytes, and immunoreactive NGF in the bronchoalveolar lavage fluid (BAL, obtained 16 h after the second antigen exposure). Treatment of rats with terbutaline (0.3 mg kg(-1), s.c. 30 min before the second antigen challenge) suppressed antigen-induced elevation of protein and eosinophil leukocytes, and reduced the concentration of NGF in BAL to values similar to those found in non-sensitized rats. 4. The present results demonstrate anti-allergic properties of terbutaline in rats that were accompanied by a marked reduction of antigen-induced NGF increase in skin and BAL, respectively. These results are compatible with the assumption that terbutaline primarily suppressed the immune response to antigen thereby attenuating the release of vasoactive mediators and the stimulation of NGF biosynthesis.     

Comparison of antiinflammatory and antiallergic drugs in the melittin- and D49 PLA2-induced mouse paw edema models.

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.     

Effect of azelastine on platelet-activating factor and antigen-induced pleurisy in rats.

The interference of azelastine with pleurisy induced by antigen was investigated in actively sensitized rats. The antigenic challenge (ovalbumin, 12 micrograms/cavity) caused early plasma leakage, which peaked within 4 h, accompanied by intense neutrophil infiltration. Pleural exudate decayed 24 h after antigen provocation, when a long-lasting increase in the number of resident eosinophils was observed. Oral pretreatment with azelastine (1-10 mg/kg) dose dependently inhibited the vasopermeation (ED50 = 4.2 mg/kg) and reduced the pleural exudate (ED50 = 6.8 mg/kg) induced by the antigen. In contrast, azelastine (10 mg/kg) failed to modify the neutrophil influx observed at 4 h and the eosinophil accumulation detected at 24 h. Azelastine was also effective against rat pleurisy induced by either platelet-activating factor (PAF-acether), histamine or serotonin. It reduced exudation and the increase in the number of mononuclear cells, neutrophils and eosinophils observed 6 h after PAF-acether. Nevertheless, antagonism of PAF-acether may not be relevant to the inhibition observed in the present model of allergic pleurisy, as the inhibition was refractory to three distinct PAF-acether receptor antagonists. In contrast, like azelastine, the histamine H1 receptor antagonist meclizine and the dual histamine and serotonin receptor antagonist cyproheptadine blocked antigen-induced exudation and failed to interfere with cell influx. We conclude that the anti-exudatory activity of oral azelastine on antigen-induced pleurisy is consistent with it exerting direct effects against vasoactive amines, but is not related to an effect against leucocyte infiltration nor to its ability to inhibit PAF-acether.     

Pharmacological modulation of 2-methyl-carbamate-PAF induced rat paw oedema

Intraplantar injections of 2-methyl-carbamate-PAF (2-MC) (0.125-16.0 micrograms/paw) into the rat paw were followed by a bell-shaped dose response curve for inflammatory oedema, with an ascending phase at 0.125-2.0 micrograms/paw, and a descending phase at 4.0-16.0 micrograms/paw. The inflammatory response to 2-MC was partially inhibited by pre-treatment with aspirin (200 mg kg-1), NDGA (100 mg kg-1), dexamethasone (0.1 mg kg-1), verapamil (50 mg kg-1) and by a specific PAF antagonist BN 52021 (5-10 mg kg-1). The cyclo-oxygenase inhibitors indomethacin (2 mg kg-1) and piroxicam (1.8 mg kg-1) as well as antihistamine meclizine (40 mg kg-1) and ranitidine (50 mg kg-1) failed to block the oedematogenic response to 2-MC. Our data suggest that 2-MC induced rat paw oedema is mediated by PAF-acether receptors and is partially dependent on arachidonate lipoxygenase pathway and extracellular Ca2+.     

The effect of some new antihistamines on the anaphylactic microshock of the guinea-pig

The dose/response curves for the protective effects of the new antihistamine compounds trimeprazine, 10-(3-diethylamino-2-methylpropyl)phenothiazine 1,1-dioxide hydrochloride (oxomemazine hydrochloride), cyproheptadine, homochlorcyclizine and methotrimeprazine against the anaphylactic microshock of the guinea-pig were similar to that of promethazine. The first three compounds, however, protected at lower doses than promethazine (5 to 10 μg/kg). The protective effect of cyproheptadine lasted longer than 24 hr.     

The anti-allergic activity of the acetate fraction of Schinus terebinthifolius leaves in IgE induced mice paw edema and pleurisy

Schinus is a genus of the Anacardiaceae family and contains Schinus terebinthifolius, the Brazilian pepper tree that is widely used in folk medicine. We investigate the anti-allergic activity of the ethyl acetate fraction of S. terebinthifolius Raddi (ST fraction). HPLC analysis reveled that gallic acid, methyl gallate and 1,2,3,4,6-pentagalloylglucose are the major aromatic components of the fraction. Oral pre-treatment with the ST fraction (100 mg/kg) significantly inhibited paw edema induced by compound 48/80 (100 ng/paw) and to a lesser extent, the allergic paw edema (OVA, 3 mug/paw). The ST fraction (100 and 200 mg/kg) also inhibited the edema induced by histamine (100 mug/paw), preventing mast cell degranulation and, consequently, histamine release in Wistar rat peritoneal mast cells induced by C 48/80 (5 mug/mL). This histamine inhibition was also observed after mast cell pre-treatment with both methyl gallate and 1,2,3,4,6-pentagalloylglucose (100 mug/mL), the isolated compounds from the ethyl acetate fraction. Pre-treatment with the ST fraction (100 mg/kg) significantly inhibited total leukocyte and eosinophil accumulation in pleural cavities 24 h after the intrathoracic injection of OVA (12.5 mug/cavity). This effect was related to the inhibition of CCL11/eotaxin and CCL5/RANTES in pleural lavage fluid. Pre-treatment with this fraction (100 mg/kg) failed to reduce the cell influx that was observed after LPS-injection into pleural cavity (250 ng/cavity). These findings demonstrate the anti-allergic effect of the ST fraction, which includes the inhibition of edema formation and histamine release caused by mast cell degranulation and eosinophil influx into the pleural cavity probably reflected by the decreased levels of chemokines in recovered pleural lavage fluid.     

Interference of azelastine with anaphylaxis induced by ovalbumin challenge in actively sensitized rats.

The inhibition of the haematological alterations and prevention of death due to systemic anaphylaxis after antigen challenge were investigated in rats after various drug treatments. The i.v. injection of ovalbumin (250 micrograms/kg) into actively sensitized rats induced marked thrombocytopenia and haemoconcentration within 5 min and significant leukocytosis within 30 min, lasting for 2 h after the challenge. Pretreatment with meclizine or terfenadine (15-30 mg/kg i.p.) inhibited antigen-induced haemoconcentration, whereas WEB 2086 (2-10 mg/kg i.p.) and PCA 4248 (5-10 mg/kg p.o.), two platelet-activating factor (PAF) antagonists, interfered with thrombocytopenia only. Azelastine (1-20 mg/kg p.o.) dose dependently inhibited antigen-induced haemoconcentration and thrombocytopenia but failed to block leukocytosis. Azelastine also inhibited the thrombocytopenia observed after the i.v. administration of PAF (4 micrograms/kg). Administration of ovalbumin at a dose of 1.5 mg/kg resulted in a lethal anaphylactic reaction in about 85% of the rats. Pretreatment with WEB 2086 (10 mg/kg i.p.), meclizine (30 mg/kg i.p.) or both increased the survival rate from 15 to 57, 68 and 87%, respectively. Azelastine alone (20 mg/kg p.o.) completely blocked the lethal reaction. It was concluded that the ability of azelastine to antagonize histamine and PAF is important for its effectiveness against anaphylactic shock.     

In vitro and in vivo antiallergic effects of Glycyrrhiza glabra and its components

Licorice (Glycyrrhiza glabra L., Leguminosae) is frequently used in traditional medicine to treat inflammatory and allergic diseases. In this study, the main components (glycyrrhizin, 18beta-glycyrrhetinic acid, isoliquiritin, and liquiritigenin) were isolated from licorice, and their anti-allergic effects, such as antiscratching behavior and IgE production-inhibitory activity, were evaluated both in vitro and in vivo. Liquiritigenin and 18beta-glycyrrhetinic acid most potently inhibited the degranulation of RBL-2H3 cells induced by IgE with the antigen (DNP-HSA) and rat peritoneal mast cells induced by compound 48/80. Liquiritigenin and 18beta-glycyrrhetinic acid potently inhibited the passive cutaneous anaphylactic reaction as well as the scratching behavior in mice induced by compound 48/80. These components inhibited the production of IgE in ovalbumin-induced asthma mice but liquiritigenin had little effect. This suggests that the antiallergic effects of licorice are mainly due to glycyrrhizin, 18beta-glycyrrhetinic acid, and liquiritigenin, which can relieve IgE-induced allergic diseases such as dermatitis and asthma.     

Anti-allodynic property of flavonoid myricitrin in models of persistent inflammatory and neuropathic pain in mice

The aim of the present study was to investigate the effects of myricitrin, a flavonoid with anti-inflammatory and antinociceptive action, upon persistent neuropathic and inflammatory pain. The neuropathic pain was caused by a partial ligation (2/3) of the sciatic nerve and the inflammatory pain was induced by an intraplantar (i.pl.) injection of 20 microL of complete Freund's adjuvant (CFA) in adult Swiss mice (25-35 g). Seven days after sciatic nerve constriction and 24 h after CFA i.pl. injection, mouse pain threshold was evaluated through tactile allodynia, using Von Frey Hair (VFH) filaments. Further analyses performed in CFA-injected mice were paw edema measurement, leukocytes infiltration, morphological changes and myeloperoxidase (MPO) enzyme activity. The intraperitoneal (i.p.) treatment with myricitrin (30 mg/kg) significantly decreased the paw withdrawal response in persistent neuropathic and inflammatory pain and decreased mouse paw edema. CFA injection increased 4-fold MPO activity and 27-fold the number of neutrophils in the mouse paw after 24 h. Myricitrin strongly reduced MPO activity, returning to basal levels; however, it did not reduce neutrophils migration. In addition, myricitrin treatment decreased morphological alterations to the epidermis and dermis papilar of mouse paw. Together these results indicate that myricitrin produces pronounced anti-allodynic and anti-edematogenic effects in two models of chronic pain in mice. Considering that few drugs are currently available for the treatment of chronic pain, the present results indicate that myricitrin might be potentially interesting in the development of new clinically relevant drugs for the management of this disorder.     

Differential inhibition by two hetrazepine PAF antagonists of acute inflammation in the mouse.

1. The injection of 100 or 300 micrograms of carrageenin into the mouse paw or pleural cavity produced a delayed inflammatory reaction at 48 h while platelet activating factor (PAF)-induced paw oedema and pleurisy were maximal 30 min after its injection. 2. The PAF antagonist, WEB 2086, failed to inhibit mouse paw oedema and pleurisy induced by PAF, but reduced the first phase of oedema (1-4 h) induced by carrageenin without interfering with the second one (48-72 h). In contrast, another structurally-related PAF antagonist, WEB 2170, inhibited dose-dependently both oedema and pleurisy induced by PAF and by carrageenin (48 h). 3. Repeated injections of PAF into the mouse paw or pleural cavity led to significant autodesensitization. The animals desensitized to PAF and injected with carrageenin also displayed a significantly reduced oedema. 4. Our results suggest that PAF may be involved in the inflammatory response to carrageenin in mice. Furthermore, because the different receptor antagonists displayed distinct effects against PAF itself, different sites for in vivo interaction of PAF are available and are species- and drug-dependent.