The absence of the leukotriene B 4 receptor BLT1 attenuates peripheral inflammation and spinal nociceptive processing fo
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MOLECULAR PAIN
RESEARCH
Open Access
The absence of the leukotriene B4 receptor BLT1 attenuates peripheral inflammation and spinal nociceptive processing following intraplantar formalin injury Miho Asahara1, Nobuko Ito1*, Takehiko Yokomizo2, Motonao Nakamura3, Takao Shimizu4,5 and Yoshitsugu Yamada1
Abstract Background: Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, and its biological effects are mediated primarily through the high affinity LTB4 receptor BLT1. Although numerous studies have reported that LTB4-BLT1 signaling is involved in inflammatory diseases, the role of BLT1 signaling in pain remains undefined. To clarify the role of LTB4-BLT1 signaling in acute inflammatory pain induced by tissue injury, we performed pain behavioral analysis and assessment of local inflammation induced by peripheral formalin injections in BLT1 knockout mice. We examined the phosphorylation of cAMP response element-binding protein (CREB) in the spinal cord both in wild-type and BLT1 knockout mice because phosphorylation of CREB in spinal cord neurons is important for nociceptive sensitization following peripheral injury. We also examined the effect of a BLT1 antagonist on formalin-induced pain responses in mice. Results: BLT1 knockout mice exhibited markedly attenuated nociceptive responses induced by intraplantar formalin injections. Edema formation and neutrophil infiltration in the paw were significantly decreased in BLT1 knockout mice compared with wild-type mice. Phosphorylation of CREB in the spinal cord after the intraplantar formalin injection was decreased in BLT1 knockout mice. In addition, mice pretreated with a BLT1 antagonist showed reduced nociception and attenuated CREB phosphorylation in the spinal cord after the formalin injection. Conclusions: Our data suggest that LTB4-BLT1 axis contributes not only to the peripheral inflammation but also to the neuronal activation in the spinal cord induced by intraplantar formalin injections. Thus, LTB4-BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury. Keywords: Inflammation, Leukotriene, Formalin test, Sensitization
Background Leukotriene B4 (LTB4; 5(S),12(R),-dihydroxy-6,14-cis-8,10trans-eicosatetraenoic acid), a metabolite of arachidonic acid catalyzed by 5-lipoxygenase and leukotriene A4 hydrolase, is a potent lipid chemoattractant responsible for recruitment of inflammatory cells to inflammatory sites [1]. The potent biological effects of LTB4 are mediated primarily through a high affinity interaction with the G-protein-coupled receptor termed LTB4 receptor * Correspondence: [email protected] 1 Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan Full list of author information is available at the end of the article
type 1 (BLT1) [2]. BLT1 is expressed in a variety of cells, including macrophages and their precursors, monocytes, as well as neutrophils, differentiated T cells and osteoclasts [3,4]. We and others established BLT1 knockout
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