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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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Intrathecal administration of PD-98059 inhibits formalin (5%, 50 μl, i.p.)-induced inflammatory nociception. (A) Time course of formalin-induced nociceptive behavior. The nociceptive behavior by formalin injection was significantly inhibited by intrathecal administration of PD-98059 in a dose dependent manner. Values are expressed as mean ± SEM. *P < 0.01, and **P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated). (B) Total times of nociceptive behavior were remarkably blocked during phase II, but not during phase I by intrathecal administration of PD-98059 in a dose-related fashion following intraplantar injection of formalin. Values are expressed mean ± SEM. *P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated).
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Figure 6: Intrathecal administration of PD-98059 inhibits formalin (5%, 50 μl, i.p.)-induced inflammatory nociception. (A) Time course of formalin-induced nociceptive behavior. The nociceptive behavior by formalin injection was significantly inhibited by intrathecal administration of PD-98059 in a dose dependent manner. Values are expressed as mean ± SEM. *P < 0.01, and **P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated). (B) Total times of nociceptive behavior were remarkably blocked during phase II, but not during phase I by intrathecal administration of PD-98059 in a dose-related fashion following intraplantar injection of formalin. Values are expressed mean ± SEM. *P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated).

Mentions: After intraplantar injection of formalin, nociceptive behavior increased and p-ERK expression was up-regulated, mainly in DH neurons of L4-L5 spinal segments, but not in microglia and astrocytes. The elevated nociceptive response and p-ERK expression were remarkably reduced by i.p. administration of EP (Figures 1 and 3). These results support the hypothesis that neuronal p-ERK expression may contribute to formalin-induced nociception. To address this issue, we directly introduced the MEK inhibitor, PD-98059, to subarachnoid space of normal rats. In the vehicle-treated rats, the duration of nociceptive response by formalin stimulation peaked at 36–40 minutes (34.4 ± 5.3 seconds/minute), and then gradually declined. Total duration of nociceptive behavior during phase II was 213.0 ± 32.7 seconds (Figures 1A and 1B) similar to the result of Figure 1B. However, these nociceptive responses were almost completely blocked by the i.t. administration of PD-98059 in a dose-dependent manner in peak time (5 μg, 19.7 ± 5.8 seconds/minute; 10.0 μg, 11.3 ± 5.0 seconds/minute), and total duration of nociceptive behavior (5 μg, 96.0 ± 26.7 seconds/minute; 10.0 μg, 64.0 ± 19.1 seconds/minute) during phase II was also decreased (Figures 6A and B). These results indicate that i.t. introduction of PD-98059 inhibits formalin-induced inflammatory pain.


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)

Intrathecal administration of PD-98059 inhibits formalin (5%, 50 μl, i.p.)-induced inflammatory nociception. (A) Time course of formalin-induced nociceptive behavior. The nociceptive behavior by formalin injection was significantly inhibited by intrathecal administration of PD-98059 in a dose dependent manner. Values are expressed as mean ± SEM. *P < 0.01, and **P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated). (B) Total times of nociceptive behavior were remarkably blocked during phase II, but not during phase I by intrathecal administration of PD-98059 in a dose-related fashion following intraplantar injection of formalin. Values are expressed mean ± SEM. *P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 6: Intrathecal administration of PD-98059 inhibits formalin (5%, 50 μl, i.p.)-induced inflammatory nociception. (A) Time course of formalin-induced nociceptive behavior. The nociceptive behavior by formalin injection was significantly inhibited by intrathecal administration of PD-98059 in a dose dependent manner. Values are expressed as mean ± SEM. *P < 0.01, and **P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated). (B) Total times of nociceptive behavior were remarkably blocked during phase II, but not during phase I by intrathecal administration of PD-98059 in a dose-related fashion following intraplantar injection of formalin. Values are expressed mean ± SEM. *P < 0.01 vs. control rats (vehicle-pretreated and formalin-treated).
Mentions: After intraplantar injection of formalin, nociceptive behavior increased and p-ERK expression was up-regulated, mainly in DH neurons of L4-L5 spinal segments, but not in microglia and astrocytes. The elevated nociceptive response and p-ERK expression were remarkably reduced by i.p. administration of EP (Figures 1 and 3). These results support the hypothesis that neuronal p-ERK expression may contribute to formalin-induced nociception. To address this issue, we directly introduced the MEK inhibitor, PD-98059, to subarachnoid space of normal rats. In the vehicle-treated rats, the duration of nociceptive response by formalin stimulation peaked at 36–40 minutes (34.4 ± 5.3 seconds/minute), and then gradually declined. Total duration of nociceptive behavior during phase II was 213.0 ± 32.7 seconds (Figures 1A and 1B) similar to the result of Figure 1B. However, these nociceptive responses were almost completely blocked by the i.t. administration of PD-98059 in a dose-dependent manner in peak time (5 μg, 19.7 ± 5.8 seconds/minute; 10.0 μg, 11.3 ± 5.0 seconds/minute), and total duration of nociceptive behavior (5 μg, 96.0 ± 26.7 seconds/minute; 10.0 μg, 64.0 ± 19.1 seconds/minute) during phase II was also decreased (Figures 6A and B). These results indicate that i.t. introduction of PD-98059 inhibits formalin-induced inflammatory pain.

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