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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

Change of nociceptive response and hind paw edema following ethyl pyruvate (EP) administration.(A) Effects of the systemic administration of ethyl pyruvate (EP) (10, 50, and 100 mg/kg) on paw licking and lifting responses following intraplantar injection of formalin (5%, 50 μl) into the hind paw. The rats receiving saline vehicle showed typical biphasic nociceptive behavior. While phase I nociceptive response was similar between the saline- and EP-injected rats, phase II nociceptive behavior was significantly reduced by EP administration 1 hour prior to formalin injection. All results are presented as mean ± SEM. Student's t test was performed at each time point after formalin injection. Values are expressed as mean ± SEM. *P < 0.01; **P < 0.05 vs. control rats (saline-pretreated and formalin-treated). Saline (n = 15), EP 10 mg/kg (n = 14), 50 mg/kg (n = 10), and 100 mg/kg (n = 13). (B) Total time of nociceptive behaviors during phase II. Total times of licking and lifting were attenuated by EP in a dose-related fashion following intraplantar injection of formalin. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated). (C) Effects of EP on the magnitude of hind paw edema following formalin injection. An index of paw edema was calculated as the mean difference of paw thickness (thickness of the ipsilateral paw after injection/thickness of the ipsilateral paw before injection × 100). EP significantly reduced formalin-induced edema compared to the control. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).
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Figure 1: Change of nociceptive response and hind paw edema following ethyl pyruvate (EP) administration.(A) Effects of the systemic administration of ethyl pyruvate (EP) (10, 50, and 100 mg/kg) on paw licking and lifting responses following intraplantar injection of formalin (5%, 50 μl) into the hind paw. The rats receiving saline vehicle showed typical biphasic nociceptive behavior. While phase I nociceptive response was similar between the saline- and EP-injected rats, phase II nociceptive behavior was significantly reduced by EP administration 1 hour prior to formalin injection. All results are presented as mean ± SEM. Student's t test was performed at each time point after formalin injection. Values are expressed as mean ± SEM. *P < 0.01; **P < 0.05 vs. control rats (saline-pretreated and formalin-treated). Saline (n = 15), EP 10 mg/kg (n = 14), 50 mg/kg (n = 10), and 100 mg/kg (n = 13). (B) Total time of nociceptive behaviors during phase II. Total times of licking and lifting were attenuated by EP in a dose-related fashion following intraplantar injection of formalin. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated). (C) Effects of EP on the magnitude of hind paw edema following formalin injection. An index of paw edema was calculated as the mean difference of paw thickness (thickness of the ipsilateral paw after injection/thickness of the ipsilateral paw before injection × 100). EP significantly reduced formalin-induced edema compared to the control. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).

Mentions: Plantar injection of formalin produces an acute inflammatory nociceptive response [28,29]. In present study, the number of nociceptive responses were counted and totaled in 5 minute intervals for 60 minutes following formalin administration (5%, 50 μl). Saline-treated control rats displayed discrete biphasic behavioral responses consisting of an early short-lasting response (phase I, 0–10 minutes post-injection), followed by a late, prolonged response (phase II, approximately 16–60 minutes post-injection). These two phases were separated by a quiescent period (11–15 minutes post-injection) (Figures 1A and 1B) [28,29]. The duration of licking, lifting, and rubbing of the ipsilateral hind paw, which were considered to be nociceptive behaviors in the formalin model, peaked around 36–40 minutes after formalin intraplantar injection with maximal nociceptive behavior per minute of 32.6 ± 3.4 seconds, which was followed by a gradually decline (Figure 1A). The nociceptive behavior was compared between the saline- and EP [10, 50, and 100 mg/kg, intraperitoneal (i.p.)]-administrated rats. Nociceptive behavior by subcutaneous irritation during phase I was not different between the groups, but during phase II, was remarkably inhibited in the EP-administrated rats in a dose-dependent manner (Figure 1A). The total number of nociceptive responses during phase II after formalin injection in the saline pre-treatment group was 163.2 ± 18.6 seconds/minute. However, the total number of nociceptive responses was significantly decreased by pre-treatment of EP in a dose-dependent pattern (10 mg/kg, 117.0 ± 14.5; 50 mg/kg, 96.4 ± 11.2; 100 mg/kg, 74.0 ± 8.3; Figure 1B). I.p. injection of either saline or EP (100 mg/kg) alone, did not alter the behavior of the animals (data not shown). These results suggest that EP has an anti-nociceptive effect on formalin-induced inflammatory nociception.


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)

Change of nociceptive response and hind paw edema following ethyl pyruvate (EP) administration.(A) Effects of the systemic administration of ethyl pyruvate (EP) (10, 50, and 100 mg/kg) on paw licking and lifting responses following intraplantar injection of formalin (5%, 50 μl) into the hind paw. The rats receiving saline vehicle showed typical biphasic nociceptive behavior. While phase I nociceptive response was similar between the saline- and EP-injected rats, phase II nociceptive behavior was significantly reduced by EP administration 1 hour prior to formalin injection. All results are presented as mean ± SEM. Student's t test was performed at each time point after formalin injection. Values are expressed as mean ± SEM. *P < 0.01; **P < 0.05 vs. control rats (saline-pretreated and formalin-treated). Saline (n = 15), EP 10 mg/kg (n = 14), 50 mg/kg (n = 10), and 100 mg/kg (n = 13). (B) Total time of nociceptive behaviors during phase II. Total times of licking and lifting were attenuated by EP in a dose-related fashion following intraplantar injection of formalin. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated). (C) Effects of EP on the magnitude of hind paw edema following formalin injection. An index of paw edema was calculated as the mean difference of paw thickness (thickness of the ipsilateral paw after injection/thickness of the ipsilateral paw before injection × 100). EP significantly reduced formalin-induced edema compared to the control. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).
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Figure 1: Change of nociceptive response and hind paw edema following ethyl pyruvate (EP) administration.(A) Effects of the systemic administration of ethyl pyruvate (EP) (10, 50, and 100 mg/kg) on paw licking and lifting responses following intraplantar injection of formalin (5%, 50 μl) into the hind paw. The rats receiving saline vehicle showed typical biphasic nociceptive behavior. While phase I nociceptive response was similar between the saline- and EP-injected rats, phase II nociceptive behavior was significantly reduced by EP administration 1 hour prior to formalin injection. All results are presented as mean ± SEM. Student's t test was performed at each time point after formalin injection. Values are expressed as mean ± SEM. *P < 0.01; **P < 0.05 vs. control rats (saline-pretreated and formalin-treated). Saline (n = 15), EP 10 mg/kg (n = 14), 50 mg/kg (n = 10), and 100 mg/kg (n = 13). (B) Total time of nociceptive behaviors during phase II. Total times of licking and lifting were attenuated by EP in a dose-related fashion following intraplantar injection of formalin. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated). (C) Effects of EP on the magnitude of hind paw edema following formalin injection. An index of paw edema was calculated as the mean difference of paw thickness (thickness of the ipsilateral paw after injection/thickness of the ipsilateral paw before injection × 100). EP significantly reduced formalin-induced edema compared to the control. Values are expressed as mean ± SEM. *P < 0.01 vs. control rats (saline-pretreated and formalin-treated).
Mentions: Plantar injection of formalin produces an acute inflammatory nociceptive response [28,29]. In present study, the number of nociceptive responses were counted and totaled in 5 minute intervals for 60 minutes following formalin administration (5%, 50 μl). Saline-treated control rats displayed discrete biphasic behavioral responses consisting of an early short-lasting response (phase I, 0–10 minutes post-injection), followed by a late, prolonged response (phase II, approximately 16–60 minutes post-injection). These two phases were separated by a quiescent period (11–15 minutes post-injection) (Figures 1A and 1B) [28,29]. The duration of licking, lifting, and rubbing of the ipsilateral hind paw, which were considered to be nociceptive behaviors in the formalin model, peaked around 36–40 minutes after formalin intraplantar injection with maximal nociceptive behavior per minute of 32.6 ± 3.4 seconds, which was followed by a gradually decline (Figure 1A). The nociceptive behavior was compared between the saline- and EP [10, 50, and 100 mg/kg, intraperitoneal (i.p.)]-administrated rats. Nociceptive behavior by subcutaneous irritation during phase I was not different between the groups, but during phase II, was remarkably inhibited in the EP-administrated rats in a dose-dependent manner (Figure 1A). The total number of nociceptive responses during phase II after formalin injection in the saline pre-treatment group was 163.2 ± 18.6 seconds/minute. However, the total number of nociceptive responses was significantly decreased by pre-treatment of EP in a dose-dependent pattern (10 mg/kg, 117.0 ± 14.5; 50 mg/kg, 96.4 ± 11.2; 100 mg/kg, 74.0 ± 8.3; Figure 1B). I.p. injection of either saline or EP (100 mg/kg) alone, did not alter the behavior of the animals (data not shown). These results suggest that EP has an anti-nociceptive effect on formalin-induced inflammatory nociception.

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