title: The role of PAF/PAFR signaling in zymosan-induced articular inflammatory hyperalgesia.
abstract: Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular hyperalgesia in a model of joint inflammation. Zymosan-induced articular hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR(-/-)). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 μg/joint), time- and PAFR-dependent articular hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB(4) as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory hyperalgesia.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Guerrero
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zaperlon
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Larissa G
authors.initials: LG
authors.lastname: Pinto
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
mesh_terms: D000818:Animals; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000473:pathology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007154:Immune System Diseases; D007249:Inflammation / Q000473:pathology*; D007592:Joint Diseases / Q000473:pathology; D007960:Leukocyte Disorders; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015054:Zymosan / Q000633:toxicity
chemical_list: D004095:Dihydropyridines; D007093:Imidazoles; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C066024:PCA 4248; C073027:modipafant; D007975:Leukotriene B4; D015054:Zymosan