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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.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.

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

ONO-4057 pretreatment affects peripheral inflammation and pCREB expression in the dorsal horn 20 min after intraplantar formalin injection. (A) Paw edema formation 1 h after formalin injection. (* p < 0.05, ONO-4057 (i.p. 0.25 mg) treated mice vs. vehicle (i.p.) treated mice, n = 5–6, unpaired Student’s t-test with Welch’s correction). (B) Quantification of Evans blue dye extravasation 1 h after formalin or vehicle injection. (** p < 0.01,*** p < 0.001, n = 6, Kruskal-Wallis with Dunn’s multiple comparison test). The number of phosphorylated CREB (pCREB)-positive neurons in the ipsilateral (C) and contralateral (D) dorsal horns of the spinal cord after intraplantar injections of formalin in mice pretreated with intraperitoneal ONO-4057 (0.25 mg, i.p.). (** p < 0.01, *** p < 0.001 vs. vehicle-pretreated mice, n = 4–5, unpaired Student’s t-test with Welch’s correction). Counts of pCREB-positive neurons in the ipsilateral (E) and contralateral (F) dorsal horn of the spinal cord after intraplantar formalin injection in mice pretreated with intraplantar ONO-4057 (2.35 μg, ipl.) injections. (* p < 0.05 vs. vehicle-pretreated mice, n = 5, unpaired Student’s t-test with Welch’s correction).
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Fig6: ONO-4057 pretreatment affects peripheral inflammation and pCREB expression in the dorsal horn 20 min after intraplantar formalin injection. (A) Paw edema formation 1 h after formalin injection. (* p < 0.05, ONO-4057 (i.p. 0.25 mg) treated mice vs. vehicle (i.p.) treated mice, n = 5–6, unpaired Student’s t-test with Welch’s correction). (B) Quantification of Evans blue dye extravasation 1 h after formalin or vehicle injection. (** p < 0.01,*** p < 0.001, n = 6, Kruskal-Wallis with Dunn’s multiple comparison test). The number of phosphorylated CREB (pCREB)-positive neurons in the ipsilateral (C) and contralateral (D) dorsal horns of the spinal cord after intraplantar injections of formalin in mice pretreated with intraperitoneal ONO-4057 (0.25 mg, i.p.). (** p < 0.01, *** p < 0.001 vs. vehicle-pretreated mice, n = 4–5, unpaired Student’s t-test with Welch’s correction). Counts of pCREB-positive neurons in the ipsilateral (E) and contralateral (F) dorsal horn of the spinal cord after intraplantar formalin injection in mice pretreated with intraplantar ONO-4057 (2.35 μg, ipl.) injections. (* p < 0.05 vs. vehicle-pretreated mice, n = 5, unpaired Student’s t-test with Welch’s correction).

Mentions: Next, we examined whether blockade of BLT1 signaling reduced peripheral inflammation. In BLT1 antagonist pretreatment group, increase of paw volume (p < 0.05) and plasma extravasation (p < 0.001) was significantly lower than that of vehicle treatment group (Figure 6A,B). We examined whether peripheral or systemic blockade of BLT1 signaling suppressed pCREB expression in the dorsal horn of the spinal cord after intraplantar formalin injection. The number of pCREB-immunoreactive neurons in the dorsal horn of mice pretreated with ONO-4057 via the intraperitoneal (Figure 6C and D) or intraplantar route (Figure 6E and F) after the formalin injection was significantly lower than that in vehicle-treated mice (p < 0.05). These results indicate that either peripheral or systemic blockade of LTB4-BLT1 signaling suppresses CREB activation in the dorsal horn and attenuates sensitization.Figure 6


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)

ONO-4057 pretreatment affects peripheral inflammation and pCREB expression in the dorsal horn 20 min after intraplantar formalin injection. (A) Paw edema formation 1 h after formalin injection. (* p < 0.05, ONO-4057 (i.p. 0.25 mg) treated mice vs. vehicle (i.p.) treated mice, n = 5–6, unpaired Student’s t-test with Welch’s correction). (B) Quantification of Evans blue dye extravasation 1 h after formalin or vehicle injection. (** p < 0.01,*** p < 0.001, n = 6, Kruskal-Wallis with Dunn’s multiple comparison test). The number of phosphorylated CREB (pCREB)-positive neurons in the ipsilateral (C) and contralateral (D) dorsal horns of the spinal cord after intraplantar injections of formalin in mice pretreated with intraperitoneal ONO-4057 (0.25 mg, i.p.). (** p < 0.01, *** p < 0.001 vs. vehicle-pretreated mice, n = 4–5, unpaired Student’s t-test with Welch’s correction). Counts of pCREB-positive neurons in the ipsilateral (E) and contralateral (F) dorsal horn of the spinal cord after intraplantar formalin injection in mice pretreated with intraplantar ONO-4057 (2.35 μg, ipl.) injections. (* p < 0.05 vs. vehicle-pretreated mice, n = 5, unpaired Student’s t-test with Welch’s correction).
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Fig6: ONO-4057 pretreatment affects peripheral inflammation and pCREB expression in the dorsal horn 20 min after intraplantar formalin injection. (A) Paw edema formation 1 h after formalin injection. (* p < 0.05, ONO-4057 (i.p. 0.25 mg) treated mice vs. vehicle (i.p.) treated mice, n = 5–6, unpaired Student’s t-test with Welch’s correction). (B) Quantification of Evans blue dye extravasation 1 h after formalin or vehicle injection. (** p < 0.01,*** p < 0.001, n = 6, Kruskal-Wallis with Dunn’s multiple comparison test). The number of phosphorylated CREB (pCREB)-positive neurons in the ipsilateral (C) and contralateral (D) dorsal horns of the spinal cord after intraplantar injections of formalin in mice pretreated with intraperitoneal ONO-4057 (0.25 mg, i.p.). (** p < 0.01, *** p < 0.001 vs. vehicle-pretreated mice, n = 4–5, unpaired Student’s t-test with Welch’s correction). Counts of pCREB-positive neurons in the ipsilateral (E) and contralateral (F) dorsal horn of the spinal cord after intraplantar formalin injection in mice pretreated with intraplantar ONO-4057 (2.35 μg, ipl.) injections. (* p < 0.05 vs. vehicle-pretreated mice, n = 5, unpaired Student’s t-test with Welch’s correction).
Mentions: Next, we examined whether blockade of BLT1 signaling reduced peripheral inflammation. In BLT1 antagonist pretreatment group, increase of paw volume (p < 0.05) and plasma extravasation (p < 0.001) was significantly lower than that of vehicle treatment group (Figure 6A,B). We examined whether peripheral or systemic blockade of BLT1 signaling suppressed pCREB expression in the dorsal horn of the spinal cord after intraplantar formalin injection. The number of pCREB-immunoreactive neurons in the dorsal horn of mice pretreated with ONO-4057 via the intraperitoneal (Figure 6C and D) or intraplantar route (Figure 6E and F) after the formalin injection was significantly lower than that in vehicle-treated mice (p < 0.05). These results indicate that either peripheral or systemic blockade of LTB4-BLT1 signaling suppresses CREB activation in the dorsal horn and attenuates sensitization.Figure 6

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.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.

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