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The absence of the leukotriene B4 receptor BLT1 attenuates peripheral inflammation and spinal nociceptive processing following intraplantar formalin injury.

Asahara M, Ito N, Yokomizo T, Nakamura M, Shimizu T, Yamada Y - Mol Pain (2015)

Bottom Line: Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, and its biological effects are mediated primarily through the high affinity LTB4 receptor BLT1.Edema formation and neutrophil infiltration in the paw were significantly decreased in BLT1 knockout mice compared with wild-type mice.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. asaharam-ane@h.u-tokyo.ac.jp.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of ONO-4057 on pain behavior in the formalin test. Time course of pain behavior in mice pretreated with intraperitoneal (i.p.) (A), intraplantar (ipl.) (C) or intrathecal (i.t.) (E) injections of ONO-4057 (* p < 0.05, *** p < 0.001 vs. vehicle). Total duration of pain behaviors in mice pretreated with i.p. (B), ipl. (D) and i.t. (F) injections of ONO-4057. (* p < 0.05, *** p < 0.001 vs. vehicle; n = 5–7; two-way ANOVA with Bonferroni post hoc tests).
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Fig5: Effects of ONO-4057 on pain behavior in the formalin test. Time course of pain behavior in mice pretreated with intraperitoneal (i.p.) (A), intraplantar (ipl.) (C) or intrathecal (i.t.) (E) injections of ONO-4057 (* p < 0.05, *** p < 0.001 vs. vehicle). Total duration of pain behaviors in mice pretreated with i.p. (B), ipl. (D) and i.t. (F) injections of ONO-4057. (* p < 0.05, *** p < 0.001 vs. vehicle; n = 5–7; two-way ANOVA with Bonferroni post hoc tests).

Mentions: The therapeutic efficacy of blocking LTB4-BLT1 signaling in formalin-injected mice was examined by pretreating mice with the BLT1 antagonist ONO-4057. To determine the potential sites of the LTB4-BLT1 signaling actions, we examined three treatment routes: intraperitoneal (i.p.), intraplantar (ipl.) and intrathecal (i.t.). In the first phase, the duration of the nociceptive responses was similar for all mice irrespective of treatment route and was not significantly different from that in the vehicle-treated group (Figure 5A,C and E). However, in the second phase, the duration of the nociceptive responses was significantly reduced for every treatment route compared with that in the vehicle-treated mice (p < 0.05) (Figure 5B,D and F). These results indicate that LTB4-BLT1 signaling is involved in nociceptive responses not only at peripheral sites, but also in the spinal cord.Figure 5


The absence of the leukotriene B4 receptor BLT1 attenuates peripheral inflammation and spinal nociceptive processing following intraplantar formalin injury.

Asahara M, Ito N, Yokomizo T, Nakamura M, Shimizu T, Yamada Y - Mol Pain (2015)

Effects of ONO-4057 on pain behavior in the formalin test. Time course of pain behavior in mice pretreated with intraperitoneal (i.p.) (A), intraplantar (ipl.) (C) or intrathecal (i.t.) (E) injections of ONO-4057 (* p < 0.05, *** p < 0.001 vs. vehicle). Total duration of pain behaviors in mice pretreated with i.p. (B), ipl. (D) and i.t. (F) injections of ONO-4057. (* p < 0.05, *** p < 0.001 vs. vehicle; n = 5–7; two-way ANOVA with Bonferroni post hoc tests).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4363055&req=5

Fig5: Effects of ONO-4057 on pain behavior in the formalin test. Time course of pain behavior in mice pretreated with intraperitoneal (i.p.) (A), intraplantar (ipl.) (C) or intrathecal (i.t.) (E) injections of ONO-4057 (* p < 0.05, *** p < 0.001 vs. vehicle). Total duration of pain behaviors in mice pretreated with i.p. (B), ipl. (D) and i.t. (F) injections of ONO-4057. (* p < 0.05, *** p < 0.001 vs. vehicle; n = 5–7; two-way ANOVA with Bonferroni post hoc tests).
Mentions: The therapeutic efficacy of blocking LTB4-BLT1 signaling in formalin-injected mice was examined by pretreating mice with the BLT1 antagonist ONO-4057. To determine the potential sites of the LTB4-BLT1 signaling actions, we examined three treatment routes: intraperitoneal (i.p.), intraplantar (ipl.) and intrathecal (i.t.). In the first phase, the duration of the nociceptive responses was similar for all mice irrespective of treatment route and was not significantly different from that in the vehicle-treated group (Figure 5A,C and E). However, in the second phase, the duration of the nociceptive responses was significantly reduced for every treatment route compared with that in the vehicle-treated mice (p < 0.05) (Figure 5B,D and F). These results indicate that LTB4-BLT1 signaling is involved in nociceptive responses not only at peripheral sites, but also in the spinal cord.Figure 5

Bottom Line: Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, and its biological effects are mediated primarily through the high affinity LTB4 receptor BLT1.Edema formation and neutrophil infiltration in the paw were significantly decreased in BLT1 knockout mice compared with wild-type mice.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan. asaharam-ane@h.u-tokyo.ac.jp.

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.

No MeSH data available.


Related in: MedlinePlus