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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

Attenuation of formalin-induced pain behavior in LTB4receptor type 1 knockout (BLT1KO) mice. (A) Time course of pain behaviors after formalin injection (* p < 0.05, **** p < 0.0001 vs. BLT1-wild-type (BLT1WT) mice). (B) Total duration of pain behaviors during the 1st (0–10 min) and the 2nd phases (11–40 min) (*** p < 0.001 vs. WT mice, n = 5, a two-way ANOVA with a Bonferroni post hoc test).
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Fig1: Attenuation of formalin-induced pain behavior in LTB4receptor type 1 knockout (BLT1KO) mice. (A) Time course of pain behaviors after formalin injection (* p < 0.05, **** p < 0.0001 vs. BLT1-wild-type (BLT1WT) mice). (B) Total duration of pain behaviors during the 1st (0–10 min) and the 2nd phases (11–40 min) (*** p < 0.001 vs. WT mice, n = 5, a two-way ANOVA with a Bonferroni post hoc test).

Mentions: To evaluate the tissue injury-induced acute nociceptive response in BLT1 knockout (BLT1KO) mice, we performed the formalin test. Intraplantar injections of formalin produced a typical biphasic pain response during a 40 min observational period (first phase, 0–10 min after formalin injection; second phase, 11–40 min after formalin injection) in BLT1WT as well as BLT1KO mice (Figure 1A). The time spent licking, biting and flinching was compared at every 5 min interval and no significant differences were observed for up to 25 min after the formalin injection (Figure 1A). However, from 25 to 35 min after the formalin injection, a significant difference between the WT and BLT1 KO mice was observed (p < 0.05). During the first phase, both BLT1WT and BLT1KO mice spent equal amounts of time performing nociceptive responses (Figure 1B). However, in the second phase, the formalin-induced pain behavior was significantly attenuated in BLT1 KO mice compared with that in WT mice (p < 0.001) (Figure 1B). In naïve BLT1KO mice, thermal and mechanical responses were examined by application of radiant heat (Ugo Basil, Italy) or various weights of von-Frey filaments (Stoelting, Wood Dale, IL, USA) to the hind paw and the withdrawal latencies were calculated. Both the calculated thermal and mechanical responses were identical to those observed in the BLT1WT littermates (data not shown).Figure 1


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)

Attenuation of formalin-induced pain behavior in LTB4receptor type 1 knockout (BLT1KO) mice. (A) Time course of pain behaviors after formalin injection (* p < 0.05, **** p < 0.0001 vs. BLT1-wild-type (BLT1WT) mice). (B) Total duration of pain behaviors during the 1st (0–10 min) and the 2nd phases (11–40 min) (*** p < 0.001 vs. WT mice, n = 5, a two-way ANOVA with a Bonferroni post hoc test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4363055&req=5

Fig1: Attenuation of formalin-induced pain behavior in LTB4receptor type 1 knockout (BLT1KO) mice. (A) Time course of pain behaviors after formalin injection (* p < 0.05, **** p < 0.0001 vs. BLT1-wild-type (BLT1WT) mice). (B) Total duration of pain behaviors during the 1st (0–10 min) and the 2nd phases (11–40 min) (*** p < 0.001 vs. WT mice, n = 5, a two-way ANOVA with a Bonferroni post hoc test).
Mentions: To evaluate the tissue injury-induced acute nociceptive response in BLT1 knockout (BLT1KO) mice, we performed the formalin test. Intraplantar injections of formalin produced a typical biphasic pain response during a 40 min observational period (first phase, 0–10 min after formalin injection; second phase, 11–40 min after formalin injection) in BLT1WT as well as BLT1KO mice (Figure 1A). The time spent licking, biting and flinching was compared at every 5 min interval and no significant differences were observed for up to 25 min after the formalin injection (Figure 1A). However, from 25 to 35 min after the formalin injection, a significant difference between the WT and BLT1 KO mice was observed (p < 0.05). During the first phase, both BLT1WT and BLT1KO mice spent equal amounts of time performing nociceptive responses (Figure 1B). However, in the second phase, the formalin-induced pain behavior was significantly attenuated in BLT1 KO mice compared with that in WT mice (p < 0.001) (Figure 1B). In naïve BLT1KO mice, thermal and mechanical responses were examined by application of radiant heat (Ugo Basil, Italy) or various weights of von-Frey filaments (Stoelting, Wood Dale, IL, USA) to the hind paw and the withdrawal latencies were calculated. Both the calculated thermal and mechanical responses were identical to those observed in the BLT1WT littermates (data not shown).Figure 1

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