Limits...
PD98059 Influences Immune Factors and Enhances Opioid Analgesia in Model of Neuropathy.

Rojewska E, Popiolek-Barczyk K, Kolosowska N, Piotrowska A, Zychowska M, Makuch W, Przewlocka B, Mika J - PLoS ONE (2015)

Bottom Line: The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy.Summing up, PD98059 diminished pain and increased the effectiveness of opioids in neuropathy.The inhibition of MEKs might inactivate a variety of cell signaling pathways that are implicated in nociception.

View Article: PubMed Central - PubMed

Affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

ABSTRACT
Neuropathic pain treatment remains challenging due to ineffective therapy and resistance to opioid analgesia. Mitogen-activated protein kinase kinase (MAPKK) have been identified as the crucial regulators of pro- and antinociceptive factors. We used PD98059, an inhibitor of the MAPKK family members MEK1/2. The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy. Moreover, we examined how PD98059 influences selected members of cellular pathways and cytokines. The PD98059 (2.5 mcg) was intrathecally preemptively administered before chronic constriction injury (CCI), and then once daily for 7 days. Additionally, at day 7 after CCI the PD98059-treated rats received a single injection of opioids. Using Western blot and qRT-PCR techniques in PD98059-treated rats we analyzed the mRNA and/or protein level of p38, ERK1/2, JNK, NF-kappaB, IL-1beta, IL-6, iNOS and IL-10 in the lumbar spinal cord. Our results indicate that PD98059 has an analgesic effects and potentiates morphine and/or buprenorphine analgesia. Parallel we observed that PD98059 inhibit upregulation of the CCI-elevated p38, ERK1/2, JNK and NF-kappaB protein levels. Moreover, PD98059 also prevented increase of pro- (IL-1beta, IL-6, and iNOS) but enhances anti-nociceptive (IL-10) factors. Summing up, PD98059 diminished pain and increased the effectiveness of opioids in neuropathy. The inhibition of MEKs might inactivate a variety of cell signaling pathways that are implicated in nociception.

No MeSH data available.


Related in: MedlinePlus

Effect of PD98059 on the p38, ERK1/2, JNK and NF-kappaB protein level in neuropathic pain.Effect of PD98059 (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the protein levels of p38 (A), ERK1/2 (B), JNK (C) and NF-kappaB (D) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the protein levels of p38, ERK1/2, JNK and NF-kappaB during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Fig A-D: C n = 4–6; V-CCI n = 5–6; PD-CCI n = 5–7. The results for phosphorylated form of p38, ERK1/2, JNK and NF-kappaB were normalized to their total protein level in the same sample and were then expressed as a ratio of the average optical density values obtained for naïve animals. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicates a significant difference compared to the control group (C), and #p<0.05 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4591269&req=5

pone.0138583.g002: Effect of PD98059 on the p38, ERK1/2, JNK and NF-kappaB protein level in neuropathic pain.Effect of PD98059 (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the protein levels of p38 (A), ERK1/2 (B), JNK (C) and NF-kappaB (D) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the protein levels of p38, ERK1/2, JNK and NF-kappaB during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Fig A-D: C n = 4–6; V-CCI n = 5–6; PD-CCI n = 5–7. The results for phosphorylated form of p38, ERK1/2, JNK and NF-kappaB were normalized to their total protein level in the same sample and were then expressed as a ratio of the average optical density values obtained for naïve animals. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicates a significant difference compared to the control group (C), and #p<0.05 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.

Mentions: The protein levels of phosphorylated and non-phosphorylated p38, ERK1/2, JNK and NF-kappaB in the ipsilateral dorsal spinal cord (L4–L6) were examined seven days after CCI using Western blot technique. The p38 protein level (38kDa) was increased in vehicle-treated CCI-exposed rats and repeated PD98059 administration prevented its upregulation in neuropathic rats (Fig 2A). The increased level of ERK1/2 (44/42kDa) in CCI-exposed rats was not observed in group which received repeated administration PD98059 (Fig 2B). In case of JNK, the 46kDa isoform was upregulated in CCI-exposed rats (Fig 2C), however the changes of 54kDa JNK isoform was not detected (data not shown). Repeated administration of PD98059 resulted inhibition of upregulation of JNK 46kDa isoform in neuropathic rats (Fig 2C), and had no influence on JNK 54kDa isoform (data not shown). The NF-kappaB (65kDa) protein level was increased in CCI-exposed rats compared to control animals (Fig 2D) and repeated PD98059 administration prevented its upregulation in neuropathic animals (Fig 2D).


PD98059 Influences Immune Factors and Enhances Opioid Analgesia in Model of Neuropathy.

Rojewska E, Popiolek-Barczyk K, Kolosowska N, Piotrowska A, Zychowska M, Makuch W, Przewlocka B, Mika J - PLoS ONE (2015)

Effect of PD98059 on the p38, ERK1/2, JNK and NF-kappaB protein level in neuropathic pain.Effect of PD98059 (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the protein levels of p38 (A), ERK1/2 (B), JNK (C) and NF-kappaB (D) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the protein levels of p38, ERK1/2, JNK and NF-kappaB during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Fig A-D: C n = 4–6; V-CCI n = 5–6; PD-CCI n = 5–7. The results for phosphorylated form of p38, ERK1/2, JNK and NF-kappaB were normalized to their total protein level in the same sample and were then expressed as a ratio of the average optical density values obtained for naïve animals. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicates a significant difference compared to the control group (C), and #p<0.05 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591269&req=5

pone.0138583.g002: Effect of PD98059 on the p38, ERK1/2, JNK and NF-kappaB protein level in neuropathic pain.Effect of PD98059 (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the protein levels of p38 (A), ERK1/2 (B), JNK (C) and NF-kappaB (D) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the protein levels of p38, ERK1/2, JNK and NF-kappaB during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Fig A-D: C n = 4–6; V-CCI n = 5–6; PD-CCI n = 5–7. The results for phosphorylated form of p38, ERK1/2, JNK and NF-kappaB were normalized to their total protein level in the same sample and were then expressed as a ratio of the average optical density values obtained for naïve animals. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicates a significant difference compared to the control group (C), and #p<0.05 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.
Mentions: The protein levels of phosphorylated and non-phosphorylated p38, ERK1/2, JNK and NF-kappaB in the ipsilateral dorsal spinal cord (L4–L6) were examined seven days after CCI using Western blot technique. The p38 protein level (38kDa) was increased in vehicle-treated CCI-exposed rats and repeated PD98059 administration prevented its upregulation in neuropathic rats (Fig 2A). The increased level of ERK1/2 (44/42kDa) in CCI-exposed rats was not observed in group which received repeated administration PD98059 (Fig 2B). In case of JNK, the 46kDa isoform was upregulated in CCI-exposed rats (Fig 2C), however the changes of 54kDa JNK isoform was not detected (data not shown). Repeated administration of PD98059 resulted inhibition of upregulation of JNK 46kDa isoform in neuropathic rats (Fig 2C), and had no influence on JNK 54kDa isoform (data not shown). The NF-kappaB (65kDa) protein level was increased in CCI-exposed rats compared to control animals (Fig 2D) and repeated PD98059 administration prevented its upregulation in neuropathic animals (Fig 2D).

Bottom Line: The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy.Summing up, PD98059 diminished pain and increased the effectiveness of opioids in neuropathy.The inhibition of MEKs might inactivate a variety of cell signaling pathways that are implicated in nociception.

View Article: PubMed Central - PubMed

Affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

ABSTRACT
Neuropathic pain treatment remains challenging due to ineffective therapy and resistance to opioid analgesia. Mitogen-activated protein kinase kinase (MAPKK) have been identified as the crucial regulators of pro- and antinociceptive factors. We used PD98059, an inhibitor of the MAPKK family members MEK1/2. The aim of study was to examine the influence of single and/or repeated PD98059 on nociception and opioid effectiveness in neuropathy. Moreover, we examined how PD98059 influences selected members of cellular pathways and cytokines. The PD98059 (2.5 mcg) was intrathecally preemptively administered before chronic constriction injury (CCI), and then once daily for 7 days. Additionally, at day 7 after CCI the PD98059-treated rats received a single injection of opioids. Using Western blot and qRT-PCR techniques in PD98059-treated rats we analyzed the mRNA and/or protein level of p38, ERK1/2, JNK, NF-kappaB, IL-1beta, IL-6, iNOS and IL-10 in the lumbar spinal cord. Our results indicate that PD98059 has an analgesic effects and potentiates morphine and/or buprenorphine analgesia. Parallel we observed that PD98059 inhibit upregulation of the CCI-elevated p38, ERK1/2, JNK and NF-kappaB protein levels. Moreover, PD98059 also prevented increase of pro- (IL-1beta, IL-6, and iNOS) but enhances anti-nociceptive (IL-10) factors. Summing up, PD98059 diminished pain and increased the effectiveness of opioids in neuropathy. The inhibition of MEKs might inactivate a variety of cell signaling pathways that are implicated in nociception.

No MeSH data available.


Related in: MedlinePlus