Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2

Abstract

Leukotriene B4 (LTB4) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB4-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1-9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO(-/-)) or by the selective antagonist of the LTB(4) receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO(-/-) mice. The hypernociceptive role of LTB4 was confirmed further by the demonstration that joint injection of LTB4 induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB4 production. Investigating the mechanism underlying LTB4 mediation of zymosan-induced hypernociception, LTB4-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 mug, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO(-/-) mice. The production of LTB4 induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE2 induced by LTB4. Therefore, besides reinforcing the role of endogenous LTB4 as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB4-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB4-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB4 synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…IVC; Ref. 251). Intraplantar injection of LTC 4 in the rat failed to evoke overt nociception, but it potentiated the acute nocifensive reaction induced by ␣,␤-methylene-ATP with a bell-shaped concentration-response curve (548).…”

“…In a novel inflammatory model, the ceramide-induced mechanical and heat hyperalgesia of rats was shown to be mediated by a peripheral p38-NF-B-COX-2-PGE 2 pathway (159). A role for prostanoids in the zymosan-induced joint mechanical hyperalgesia was proposed (250,251).…”

Tephrosia sinapouethyl acetate extract inhibits inflammatory pain in mice: Opioid receptor dependent inhibition of TNFαand IL-1βproduction

“…In animals, LTB 4 -induced hyperalgesia was inhibited by leukocyte depletion (Levine et al, 1984). Recently, it has been demonstrated that neutrophils are important for the hyperalgesia induced by carrageenin, zymosan and antigen-induced inflammation by further producing nociceptive mediators including LTB 4 and PGE 2 (Cunha et al, 2008b;Guerrero et al, 2008;Ting et al, 2008;Verri et al, 2009). On the other hand, it has also been described that neutrophils can reduce hyperalgesia by releasing opioids at the local inflammatory site (Cunha & Verri, 2006;Rittner et al, 2006).…”

Leveraging model-based study designs and serial micro-sampling techniques to understand the oral pharmacokinetics of the potent LTB4 inhibitor, CP-105696, for mouse pharmacology studies

“…antagonists have been developed and used successfully in preclinical models of disease, such as amelubant (Boehringer-Ingelheim) in mouse ear inflammation, transdermal chemotaxis in guinea pigs and neutropenia in various species (Birke et al, 2001) and CP-105696 (Pfizer) in atherosclerosis in mice (Aiello et al, 2002), ischemia and reperfusion injury in rats (Souza et al, 2002) and articular inflammation in mice (Guerrero et al, 2008). Unfortunately clinical trials have failed to replicate the success of preclinical studies, suggesting the need for further examination of these compounds' efficacy using different conditions and model systems in preclinical studies.…”