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Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation.

Lee MJ, Jang M, Jung HS, Kim SH, Cho IH - Mol Pain (2012)

Bottom Line: EP significantly decreased formalin-induced nociceptive behavior during phase II, the magnitude of paw edema, and the activation of c-Fos in L4-L5 spinal dorsal horn.Interestingly, the i.t. administration of PD98059, an ERK upstream kinase (MEK) inhibitor, completely blocked the formalin-induced inflammatory nociceptive responses.These results demonstrate that EP may effectively inhibit formalin-induced inflammatory nociception via the inhibition of neuronal ERK phosphorylation in the spinal dorsal horn, indicating its therapeutic potential in suppressing acute inflammatory pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy, College of Oriental Medicine, and Institute of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.

ABSTRACT

Background: Ethyl pyruvate (EP) possesses anti-inflammatory activity. However, the potential anti-nociceptive value of EP for the treatment of the inflammatory nociception is largely unknown. We investigated whether EP could have any anti-nociceptive effect on inflammatory pain, after systemic administration of EP (10, 50, and 100 mg/kg, i.p.), 1 hour before formalin (5%, 50 μl) injection into the plantar surface of the hind paws of rats.

Results: EP significantly decreased formalin-induced nociceptive behavior during phase II, the magnitude of paw edema, and the activation of c-Fos in L4-L5 spinal dorsal horn. EP also attenuated the phosphorylation of extracellular signal-regulated kinase (ERK) in the neurons of L4-L5 spinal dorsal horn after formalin injection. Interestingly, the i.t. administration of PD98059, an ERK upstream kinase (MEK) inhibitor, completely blocked the formalin-induced inflammatory nociceptive responses.

Conclusions: These results demonstrate that EP may effectively inhibit formalin-induced inflammatory nociception via the inhibition of neuronal ERK phosphorylation in the spinal dorsal horn, indicating its therapeutic potential in suppressing acute inflammatory pain.

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Phosphorylation of ERK1/2 in the DH of spinal cord (L4-L5) after saline or EP pretreatment.(A) Western blots from spinal DH. N, normal. FA, saline-pretreated and formalin- treated rats, FA + EP, EP-pretreated and formalin-treated rats. E, EP alone. (B-D) Photomicrographs showing c-Fos expression in the spinal DH from normal rats (B), saline-pretreated and formalin-treated rats (C), EP-pretreated and formalin-treated rats (D). The number enhancement of p-ERK-IR cells produced by formalin was clearly decreased in both the superficial lamina (I-II) and deep lamina (III-IV) by EP-pretreatment. Insets are high magnification of the open rectangles. Scale bar = 100 μm. (E) The number of p-ERK-IR cells in spinal DH following EP preinjection. The enhancement in the number of p-ERK positive cells produced by formalin was significantly decreased in spinal DH by EP pre-administration. The mean number of p-ERK positive cells was calculated by averaging the total numbers per each region. Values are expressed as mean ± SEM. +P < 0.01 vs. normal rats (saline-pretreated and saline-treated); *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).
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Figure 3: Phosphorylation of ERK1/2 in the DH of spinal cord (L4-L5) after saline or EP pretreatment.(A) Western blots from spinal DH. N, normal. FA, saline-pretreated and formalin- treated rats, FA + EP, EP-pretreated and formalin-treated rats. E, EP alone. (B-D) Photomicrographs showing c-Fos expression in the spinal DH from normal rats (B), saline-pretreated and formalin-treated rats (C), EP-pretreated and formalin-treated rats (D). The number enhancement of p-ERK-IR cells produced by formalin was clearly decreased in both the superficial lamina (I-II) and deep lamina (III-IV) by EP-pretreatment. Insets are high magnification of the open rectangles. Scale bar = 100 μm. (E) The number of p-ERK-IR cells in spinal DH following EP preinjection. The enhancement in the number of p-ERK positive cells produced by formalin was significantly decreased in spinal DH by EP pre-administration. The mean number of p-ERK positive cells was calculated by averaging the total numbers per each region. Values are expressed as mean ± SEM. +P < 0.01 vs. normal rats (saline-pretreated and saline-treated); *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).

Mentions: ERK 1/2 are expressed in the spinal cord and are activated in rat spinal DH neurons after inflammation [20,36]. Inhibitors of ERK signaling reduce nociceptive response in the phase II of the formalin test, suggesting a selective role for ERK 1/2 in nociceptive sensitization [20]. In addition, ERK phosphorylation is inhibited in the LPS-induced inflammation by EP administration [15]. Therefore, we investigated whether EP could produce its effects through the ERK 1/2 signaling pathway in the formalin-induced nociception. As illustrated in Figure 3A, at 36- 40 minutes after formalin treatment, we observed a clear phosphorylation of ERK 1/2 in the L4-L5 spinal DH. However, the elevated level of the phosphorylation of ERK 1/2 was decreased by EP administration (100 mg/kg, i.p.) (Figure 3A). Subsequently, we examined the spinal distribution of the phosphorylation of ERK 1/2 (Figures 3B3E). Immunohistochemical evaluation confirmed that p-ERK-IR cells in the L4-L5 spinal DH were very scarce in saline-administrated normal rats (I-IV, 12.6 ± 1.2; I-II, 12.3 ± 0.6; III-IV, 6.3 ± 0.3) (Figures 3B and 3E). The number of p-ERK-IR cells in lamina I-II of the spinal DH was significantly increased by formalin treatment (I-IV, 62.9 ± 7.2; I-II, 59.9 ± 2.7; III-IV, 19.2 ± 1.0), but these formalin-stimulated p-ERK enhancements were decreased by EP-administration (I-IV, 30.4 ± 3.8; I-II, 33.3 ± 2.2; III-IV, 13.7 ± 0.6) (Figures 3C3E).


Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation.

Lee MJ, Jang M, Jung HS, Kim SH, Cho IH - Mol Pain (2012)

Phosphorylation of ERK1/2 in the DH of spinal cord (L4-L5) after saline or EP pretreatment.(A) Western blots from spinal DH. N, normal. FA, saline-pretreated and formalin- treated rats, FA + EP, EP-pretreated and formalin-treated rats. E, EP alone. (B-D) Photomicrographs showing c-Fos expression in the spinal DH from normal rats (B), saline-pretreated and formalin-treated rats (C), EP-pretreated and formalin-treated rats (D). The number enhancement of p-ERK-IR cells produced by formalin was clearly decreased in both the superficial lamina (I-II) and deep lamina (III-IV) by EP-pretreatment. Insets are high magnification of the open rectangles. Scale bar = 100 μm. (E) The number of p-ERK-IR cells in spinal DH following EP preinjection. The enhancement in the number of p-ERK positive cells produced by formalin was significantly decreased in spinal DH by EP pre-administration. The mean number of p-ERK positive cells was calculated by averaging the total numbers per each region. Values are expressed as mean ± SEM. +P < 0.01 vs. normal rats (saline-pretreated and saline-treated); *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Phosphorylation of ERK1/2 in the DH of spinal cord (L4-L5) after saline or EP pretreatment.(A) Western blots from spinal DH. N, normal. FA, saline-pretreated and formalin- treated rats, FA + EP, EP-pretreated and formalin-treated rats. E, EP alone. (B-D) Photomicrographs showing c-Fos expression in the spinal DH from normal rats (B), saline-pretreated and formalin-treated rats (C), EP-pretreated and formalin-treated rats (D). The number enhancement of p-ERK-IR cells produced by formalin was clearly decreased in both the superficial lamina (I-II) and deep lamina (III-IV) by EP-pretreatment. Insets are high magnification of the open rectangles. Scale bar = 100 μm. (E) The number of p-ERK-IR cells in spinal DH following EP preinjection. The enhancement in the number of p-ERK positive cells produced by formalin was significantly decreased in spinal DH by EP pre-administration. The mean number of p-ERK positive cells was calculated by averaging the total numbers per each region. Values are expressed as mean ± SEM. +P < 0.01 vs. normal rats (saline-pretreated and saline-treated); *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).
Mentions: ERK 1/2 are expressed in the spinal cord and are activated in rat spinal DH neurons after inflammation [20,36]. Inhibitors of ERK signaling reduce nociceptive response in the phase II of the formalin test, suggesting a selective role for ERK 1/2 in nociceptive sensitization [20]. In addition, ERK phosphorylation is inhibited in the LPS-induced inflammation by EP administration [15]. Therefore, we investigated whether EP could produce its effects through the ERK 1/2 signaling pathway in the formalin-induced nociception. As illustrated in Figure 3A, at 36- 40 minutes after formalin treatment, we observed a clear phosphorylation of ERK 1/2 in the L4-L5 spinal DH. However, the elevated level of the phosphorylation of ERK 1/2 was decreased by EP administration (100 mg/kg, i.p.) (Figure 3A). Subsequently, we examined the spinal distribution of the phosphorylation of ERK 1/2 (Figures 3B3E). Immunohistochemical evaluation confirmed that p-ERK-IR cells in the L4-L5 spinal DH were very scarce in saline-administrated normal rats (I-IV, 12.6 ± 1.2; I-II, 12.3 ± 0.6; III-IV, 6.3 ± 0.3) (Figures 3B and 3E). The number of p-ERK-IR cells in lamina I-II of the spinal DH was significantly increased by formalin treatment (I-IV, 62.9 ± 7.2; I-II, 59.9 ± 2.7; III-IV, 19.2 ± 1.0), but these formalin-stimulated p-ERK enhancements were decreased by EP-administration (I-IV, 30.4 ± 3.8; I-II, 33.3 ± 2.2; III-IV, 13.7 ± 0.6) (Figures 3C3E).

Bottom Line: EP significantly decreased formalin-induced nociceptive behavior during phase II, the magnitude of paw edema, and the activation of c-Fos in L4-L5 spinal dorsal horn.Interestingly, the i.t. administration of PD98059, an ERK upstream kinase (MEK) inhibitor, completely blocked the formalin-induced inflammatory nociceptive responses.These results demonstrate that EP may effectively inhibit formalin-induced inflammatory nociception via the inhibition of neuronal ERK phosphorylation in the spinal dorsal horn, indicating its therapeutic potential in suppressing acute inflammatory pain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy, College of Oriental Medicine, and Institute of Oriental Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.

ABSTRACT

Background: Ethyl pyruvate (EP) possesses anti-inflammatory activity. However, the potential anti-nociceptive value of EP for the treatment of the inflammatory nociception is largely unknown. We investigated whether EP could have any anti-nociceptive effect on inflammatory pain, after systemic administration of EP (10, 50, and 100 mg/kg, i.p.), 1 hour before formalin (5%, 50 μl) injection into the plantar surface of the hind paws of rats.

Results: EP significantly decreased formalin-induced nociceptive behavior during phase II, the magnitude of paw edema, and the activation of c-Fos in L4-L5 spinal dorsal horn. EP also attenuated the phosphorylation of extracellular signal-regulated kinase (ERK) in the neurons of L4-L5 spinal dorsal horn after formalin injection. Interestingly, the i.t. administration of PD98059, an ERK upstream kinase (MEK) inhibitor, completely blocked the formalin-induced inflammatory nociceptive responses.

Conclusions: These results demonstrate that EP may effectively inhibit formalin-induced inflammatory nociception via the inhibition of neuronal ERK phosphorylation in the spinal dorsal horn, indicating its therapeutic potential in suppressing acute inflammatory pain.

Show MeSH
Related in: MedlinePlus