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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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Related in: MedlinePlus

Representative photomicrographs and graph showing immunoreactivity of c-Fos in the spinal DH (L4-5) following formalin injection. (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 elevated number of c-Fos-immunorective (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 c-Fos-IR cells in spinal DH following EP pre-injection. The mean number of c-Fos-IR 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 2: Representative photomicrographs and graph showing immunoreactivity of c-Fos in the spinal DH (L4-5) following formalin injection. (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 elevated number of c-Fos-immunorective (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 c-Fos-IR cells in spinal DH following EP pre-injection. The mean number of c-Fos-IR 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: Because c-Fos, the protein product of the immediate-early gene c-fos, is a neuroactive marker that can be used to analyze nociceptive pathways [31-33], we compared the level of spinal c-Fos expression between the saline- or formalin-injected rats (n = 8/group) 36–40 minutes after formalin injection, the time at which the introduced formalin produced the maximal effects on nociceptive behavior (Figure 1A). c-Fos-immunoreactive (IR) cells were evaluated in the superficial laminae (I-II) and deep laminae (III-IV) of the DH in L4-L5 spinal cord where primary afferent fibers, from sciatic nerves innervating hind limb including the hind paw, form synapses with dorsal sensory neurons [34,35]. At 36–40 minutes after formalin injection, we confirmed the change of c-Fos expression in the ipsilateral DH of the L4-L5 spinal cord (Figure 2A). c-Fos expression was upregulated in the spinal DH of formalin-induced rats compare to normal, saline- pretreated and saline-treated rats. However, the elevated level of c-Fos expression was decreased by EP-administration (100 mg/kg, i.p.) (Figure 2A). In addition, we evaluated the anatomical distribution of c-Fos expression in spinal DH (Figures 2B2E). The c-Fos-IR in the L4-L5 spinal DH was very scarce in normal rats (I-IV, 28.9 ± 3.4; I-II, 11.3 ± 1.9; III-IV, 17.5 ± 1.8). The number of c-Fos-IR cells in the superficial and deep laminae was extensively increased following intraplantar injection of formalin (I-IV, 74.1 ± 3.4; I-II, 48.6 ± 2.3; III-IV, 25.6 ± 2.0), but the formalin-induced c-Fos-IR enhancement was significantly decreased by EP-administration (100 mg/kg, i.p.) 1 hour prior to formalin injection (I-IV, 45.9 ± 7.9; I-II,31.0 ± 6.4; III-IV, 14.9 ± 2.1) (Figures 2B2E). The number of c-Fos-IR cells in the contralateral DH was similar to that in the spinal DH of normal rats (data not shown). EP (100 mg/kg, i.p.), itself did not have any effect on c-Fos expression in the spinal cord. Taken together, the above results suggest that EP has an inhibitory action in spinal sensitization in formalin-induced acute inflammatory nociception (Figures 2B2E).


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)

Representative photomicrographs and graph showing immunoreactivity of c-Fos in the spinal DH (L4-5) following formalin injection. (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 elevated number of c-Fos-immunorective (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 c-Fos-IR cells in spinal DH following EP pre-injection. The mean number of c-Fos-IR 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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Show All Figures
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Figure 2: Representative photomicrographs and graph showing immunoreactivity of c-Fos in the spinal DH (L4-5) following formalin injection. (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 elevated number of c-Fos-immunorective (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 c-Fos-IR cells in spinal DH following EP pre-injection. The mean number of c-Fos-IR 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: Because c-Fos, the protein product of the immediate-early gene c-fos, is a neuroactive marker that can be used to analyze nociceptive pathways [31-33], we compared the level of spinal c-Fos expression between the saline- or formalin-injected rats (n = 8/group) 36–40 minutes after formalin injection, the time at which the introduced formalin produced the maximal effects on nociceptive behavior (Figure 1A). c-Fos-immunoreactive (IR) cells were evaluated in the superficial laminae (I-II) and deep laminae (III-IV) of the DH in L4-L5 spinal cord where primary afferent fibers, from sciatic nerves innervating hind limb including the hind paw, form synapses with dorsal sensory neurons [34,35]. At 36–40 minutes after formalin injection, we confirmed the change of c-Fos expression in the ipsilateral DH of the L4-L5 spinal cord (Figure 2A). c-Fos expression was upregulated in the spinal DH of formalin-induced rats compare to normal, saline- pretreated and saline-treated rats. However, the elevated level of c-Fos expression was decreased by EP-administration (100 mg/kg, i.p.) (Figure 2A). In addition, we evaluated the anatomical distribution of c-Fos expression in spinal DH (Figures 2B2E). The c-Fos-IR in the L4-L5 spinal DH was very scarce in normal rats (I-IV, 28.9 ± 3.4; I-II, 11.3 ± 1.9; III-IV, 17.5 ± 1.8). The number of c-Fos-IR cells in the superficial and deep laminae was extensively increased following intraplantar injection of formalin (I-IV, 74.1 ± 3.4; I-II, 48.6 ± 2.3; III-IV, 25.6 ± 2.0), but the formalin-induced c-Fos-IR enhancement was significantly decreased by EP-administration (100 mg/kg, i.p.) 1 hour prior to formalin injection (I-IV, 45.9 ± 7.9; I-II,31.0 ± 6.4; III-IV, 14.9 ± 2.1) (Figures 2B2E). The number of c-Fos-IR cells in the contralateral DH was similar to that in the spinal DH of normal rats (data not shown). EP (100 mg/kg, i.p.), itself did not have any effect on c-Fos expression in the spinal cord. Taken together, the above results suggest that EP has an inhibitory action in spinal sensitization in formalin-induced acute inflammatory nociception (Figures 2B2E).

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