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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 development of neuropathic pain symptoms.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 development of mechanical allodynia (A; von Frey test) and thermal hyperalgesia (B; cold plate) on days 3 and 7 after CCI. Pain was assessed using von Frey and cold plate tests 30 min after the last drug administration, and the data are presented as the means ± SEM. The inter-group differences were analyzed with ANOVA and Bonferroni’s multiple comparison test. ***p<0.001 indicates a significant difference compared to the control group (C), and #p< 0.05 or ###p<0.001 indicates a significant difference compared to the V-CCI rats (ANOVA, Bonferroni’s test). The number of animals per group—day 3: C n = 7; V-CCI n = 7; PD-CCI n = 10; day 7: C n = 17; V-CCI n = 28; PD-CCI n = 26. C, control,; V, vehicle, PD, PD98059. The a line is drawn at value that represents the cut-off.
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pone.0138583.g001: Effect of PD98059 on the development of neuropathic pain symptoms.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 development of mechanical allodynia (A; von Frey test) and thermal hyperalgesia (B; cold plate) on days 3 and 7 after CCI. Pain was assessed using von Frey and cold plate tests 30 min after the last drug administration, and the data are presented as the means ± SEM. The inter-group differences were analyzed with ANOVA and Bonferroni’s multiple comparison test. ***p<0.001 indicates a significant difference compared to the control group (C), and #p< 0.05 or ###p<0.001 indicates a significant difference compared to the V-CCI rats (ANOVA, Bonferroni’s test). The number of animals per group—day 3: C n = 7; V-CCI n = 7; PD-CCI n = 10; day 7: C n = 17; V-CCI n = 28; PD-CCI n = 26. C, control,; V, vehicle, PD, PD98059. The a line is drawn at value that represents the cut-off.

Mentions: The influence of repeated i.t. administration of PD98059 (2.5 mcg), delivered at 16 h and 1 h before ligation of the sciatic nerve and then once daily for seven days, on mechanical allodynia and thermal hyperalgesia was measured three and seven days following CCI using von Frey (Fig 1A) and cold plate (Fig 1B) tests, respectively. In CCI-exposed rats the allodynia was measured three (15.1 g ± 1.3, n = 7) and seven (14.21 g ± 0.44, n = 28) days following CCI in comparison to the control rats (25.5 g ± 0.3, n = 7 and 25.7 g ± 0.2, respectively, n = 17) (Fig 1A). Simultaneously, the hyperalgesia was observed three (11.5 s ± 1.8, n = 7) and seven (11.4 s ± 0.88, n = 28) days following CCI in comparison to the control rats (28.0 s ± 0.5, n = 7 and 28.0 s ± 0.8, n = 17, respectively) (Fig 1B).


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 development of neuropathic pain symptoms.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 development of mechanical allodynia (A; von Frey test) and thermal hyperalgesia (B; cold plate) on days 3 and 7 after CCI. Pain was assessed using von Frey and cold plate tests 30 min after the last drug administration, and the data are presented as the means ± SEM. The inter-group differences were analyzed with ANOVA and Bonferroni’s multiple comparison test. ***p<0.001 indicates a significant difference compared to the control group (C), and #p< 0.05 or ###p<0.001 indicates a significant difference compared to the V-CCI rats (ANOVA, Bonferroni’s test). The number of animals per group—day 3: C n = 7; V-CCI n = 7; PD-CCI n = 10; day 7: C n = 17; V-CCI n = 28; PD-CCI n = 26. C, control,; V, vehicle, PD, PD98059. The a line is drawn at value that represents the cut-off.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4591269&req=5

pone.0138583.g001: Effect of PD98059 on the development of neuropathic pain symptoms.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 development of mechanical allodynia (A; von Frey test) and thermal hyperalgesia (B; cold plate) on days 3 and 7 after CCI. Pain was assessed using von Frey and cold plate tests 30 min after the last drug administration, and the data are presented as the means ± SEM. The inter-group differences were analyzed with ANOVA and Bonferroni’s multiple comparison test. ***p<0.001 indicates a significant difference compared to the control group (C), and #p< 0.05 or ###p<0.001 indicates a significant difference compared to the V-CCI rats (ANOVA, Bonferroni’s test). The number of animals per group—day 3: C n = 7; V-CCI n = 7; PD-CCI n = 10; day 7: C n = 17; V-CCI n = 28; PD-CCI n = 26. C, control,; V, vehicle, PD, PD98059. The a line is drawn at value that represents the cut-off.
Mentions: The influence of repeated i.t. administration of PD98059 (2.5 mcg), delivered at 16 h and 1 h before ligation of the sciatic nerve and then once daily for seven days, on mechanical allodynia and thermal hyperalgesia was measured three and seven days following CCI using von Frey (Fig 1A) and cold plate (Fig 1B) tests, respectively. In CCI-exposed rats the allodynia was measured three (15.1 g ± 1.3, n = 7) and seven (14.21 g ± 0.44, n = 28) days following CCI in comparison to the control rats (25.5 g ± 0.3, n = 7 and 25.7 g ± 0.2, respectively, n = 17) (Fig 1A). Simultaneously, the hyperalgesia was observed three (11.5 s ± 1.8, n = 7) and seven (11.4 s ± 0.88, n = 28) days following CCI in comparison to the control rats (28.0 s ± 0.5, n = 7 and 28.0 s ± 0.8, n = 17, respectively) (Fig 1B).

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