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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 mRNA and protein level of pro-inflammatory factors (IL-1beta, iNOS, IL-6 and IL-18) and anti-inflammatory factor (IL-10) 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 mRNA and protein levels of IL-1beta (A, F), iNOS (B, G), IL-6 (C, H), IL-18 (D, I) and IL-10 (E, J) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the mRNA levels of iNOS (B) and induced expression of mRNA for IL-10 (E), but did not influence the level of IL-1beta (A), IL-6 (C) and IL-18 (D) in the spinal cord during neuropathic pain. Repeated PD98059 treatment prevent the upregulation of the protein levels of IL-1beta (F), iNOS (G), IL-6 (H) and induced IL-10 (J), but did not influence the level of IL-18 (I) in the spinal cord during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Figs A-E: C n = 4–5; V-CCI n = 6; PD-CCI n = 4–5; Figs F-J: C n = 4–6; V-CCI n = 5–8; PD-CCI n = 6–7. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicate significant differences compared to the control group (C), and ##p<0.01 and ###p<0.001 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.
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pone.0138583.g003: Effect of PD98059 on the mRNA and protein level of pro-inflammatory factors (IL-1beta, iNOS, IL-6 and IL-18) and anti-inflammatory factor (IL-10) 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 mRNA and protein levels of IL-1beta (A, F), iNOS (B, G), IL-6 (C, H), IL-18 (D, I) and IL-10 (E, J) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the mRNA levels of iNOS (B) and induced expression of mRNA for IL-10 (E), but did not influence the level of IL-1beta (A), IL-6 (C) and IL-18 (D) in the spinal cord during neuropathic pain. Repeated PD98059 treatment prevent the upregulation of the protein levels of IL-1beta (F), iNOS (G), IL-6 (H) and induced IL-10 (J), but did not influence the level of IL-18 (I) in the spinal cord during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Figs A-E: C n = 4–5; V-CCI n = 6; PD-CCI n = 4–5; Figs F-J: C n = 4–6; V-CCI n = 5–8; PD-CCI n = 6–7. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicate significant differences compared to the control group (C), and ##p<0.01 and ###p<0.001 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.

Mentions: The mRNA levels of IL-1beta, IL-6, IL-18, iNOS and IL-10 in the ipsilateral dorsal spinal cord (L4–L6) were examined seven days after CCI using qRT-PCR assay. The level of IL-1beta, iNOS and IL-18 were upregulated in CCI-exposed rats compared to control animals (Fig 3A, 3B and 3D) but the repeated PD98059 administration prevent increased of iNOS (Fig 3B) level. We observed in vehicle-treated CCI-exposed rats that the IL-6 (21 kDa) protein level was highly increased but the IL-6 mRNA level shown only tendency to increase and the repeated administration of PD98059 had not significant effect on IL-6 mRNA (Fig 3C).


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 mRNA and protein level of pro-inflammatory factors (IL-1beta, iNOS, IL-6 and IL-18) and anti-inflammatory factor (IL-10) 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 mRNA and protein levels of IL-1beta (A, F), iNOS (B, G), IL-6 (C, H), IL-18 (D, I) and IL-10 (E, J) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the mRNA levels of iNOS (B) and induced expression of mRNA for IL-10 (E), but did not influence the level of IL-1beta (A), IL-6 (C) and IL-18 (D) in the spinal cord during neuropathic pain. Repeated PD98059 treatment prevent the upregulation of the protein levels of IL-1beta (F), iNOS (G), IL-6 (H) and induced IL-10 (J), but did not influence the level of IL-18 (I) in the spinal cord during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Figs A-E: C n = 4–5; V-CCI n = 6; PD-CCI n = 4–5; Figs F-J: C n = 4–6; V-CCI n = 5–8; PD-CCI n = 6–7. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicate significant differences compared to the control group (C), and ##p<0.01 and ###p<0.001 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.
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Related In: Results  -  Collection

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

pone.0138583.g003: Effect of PD98059 on the mRNA and protein level of pro-inflammatory factors (IL-1beta, iNOS, IL-6 and IL-18) and anti-inflammatory factor (IL-10) 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 mRNA and protein levels of IL-1beta (A, F), iNOS (B, G), IL-6 (C, H), IL-18 (D, I) and IL-10 (E, J) in the ipsilateral dorsal part of the lumbar spinal cord on day 7 after CCI. PD98059 prevent the upregulation of the mRNA levels of iNOS (B) and induced expression of mRNA for IL-10 (E), but did not influence the level of IL-1beta (A), IL-6 (C) and IL-18 (D) in the spinal cord during neuropathic pain. Repeated PD98059 treatment prevent the upregulation of the protein levels of IL-1beta (F), iNOS (G), IL-6 (H) and induced IL-10 (J), but did not influence the level of IL-18 (I) in the spinal cord during neuropathic pain. The data are presented as the fold change of control. The number of individual samples per group Figs A-E: C n = 4–5; V-CCI n = 6; PD-CCI n = 4–5; Figs F-J: C n = 4–6; V-CCI n = 5–8; PD-CCI n = 6–7. Inter-group differences were analyzed using Bonferroni's multiple comparison test. *p<0.05, **p<0.01 and ***p<0.001 indicate significant differences compared to the control group (C), and ##p<0.01 and ###p<0.001 indicate significant differences compared to the V-CCI rats (ANOVA, Bonferroni’s test). C, control; V, vehicle; PD, PD98059.
Mentions: The mRNA levels of IL-1beta, IL-6, IL-18, iNOS and IL-10 in the ipsilateral dorsal spinal cord (L4–L6) were examined seven days after CCI using qRT-PCR assay. The level of IL-1beta, iNOS and IL-18 were upregulated in CCI-exposed rats compared to control animals (Fig 3A, 3B and 3D) but the repeated PD98059 administration prevent increased of iNOS (Fig 3B) level. We observed in vehicle-treated CCI-exposed rats that the IL-6 (21 kDa) protein level was highly increased but the IL-6 mRNA level shown only tendency to increase and the repeated administration of PD98059 had not significant effect on IL-6 mRNA (Fig 3C).

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