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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 opioid analgesia in a naive and neuropathic rats.Effect of repeated vehicle or PD98059 administration (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the analgesic effects of a single injection of morphine (5 mcg/5 mcl; i.t.) in CCI-exposed rats on day 7 after injury as measured by von Frey (A) and cold plate (B) in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (C, 2.5 mcg/5 mcl) and buprenorphine (D, 2.5 mcg/5 mcl) as measured by von Frey in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (E, 0.5 mcg/5 mcl) and buprenorphine (F, 2.5 mcg/5 mcl) as measured by tail flick test in naive animals. Behavioral tests were conducted 30 min after vehicle or PD98059 administration and then 30 min after a single vehicle, morphine or buprenorphine injection. Data are presented as the means ± SEM. The inter-group differences were analyzed using ANOVA and Bonferroni’s multiple comparison test. ###p<0.001 indicates a significant difference compared to the control group; $ $p<0.01 and $ $ $p<0.001 indicate significant differences compared to the repeated or single PD-treated CCI-exposed rats which received single morphine or buprenorphine injection, and °p<0.05, and °°°p<0.001 indicate significant differences between repeated or single PD-treated CCI-exposed or naive rats to repeated or single PD-treated CCI-exposed or naive rats which received single morphine or buprenorphine C, control; V, vehicle; PD, PD98059. The number of animals per group—Figs A&B: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 10, PD+M-CCI n = 7; Fig C: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 8; Fig D: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 7; Fig E: V+V-CCI n = 12; PD+V-CCI n = 10, V+M-CCI n = 7, PD+M-CCI n = 6; Fig F: V+V-CCI n = 8; PD+V-CCI n = 12, V+B-CCI n = 6, PD+B-CCI n = 6.
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pone.0138583.g004: Effect of PD98059 on opioid analgesia in a naive and neuropathic rats.Effect of repeated vehicle or PD98059 administration (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the analgesic effects of a single injection of morphine (5 mcg/5 mcl; i.t.) in CCI-exposed rats on day 7 after injury as measured by von Frey (A) and cold plate (B) in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (C, 2.5 mcg/5 mcl) and buprenorphine (D, 2.5 mcg/5 mcl) as measured by von Frey in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (E, 0.5 mcg/5 mcl) and buprenorphine (F, 2.5 mcg/5 mcl) as measured by tail flick test in naive animals. Behavioral tests were conducted 30 min after vehicle or PD98059 administration and then 30 min after a single vehicle, morphine or buprenorphine injection. Data are presented as the means ± SEM. The inter-group differences were analyzed using ANOVA and Bonferroni’s multiple comparison test. ###p<0.001 indicates a significant difference compared to the control group; $ $p<0.01 and $ $ $p<0.001 indicate significant differences compared to the repeated or single PD-treated CCI-exposed rats which received single morphine or buprenorphine injection, and °p<0.05, and °°°p<0.001 indicate significant differences between repeated or single PD-treated CCI-exposed or naive rats to repeated or single PD-treated CCI-exposed or naive rats which received single morphine or buprenorphine C, control; V, vehicle; PD, PD98059. The number of animals per group—Figs A&B: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 10, PD+M-CCI n = 7; Fig C: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 8; Fig D: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 7; Fig E: V+V-CCI n = 12; PD+V-CCI n = 10, V+M-CCI n = 7, PD+M-CCI n = 6; Fig F: V+V-CCI n = 8; PD+V-CCI n = 12, V+B-CCI n = 6, PD+B-CCI n = 6.

Mentions: In CCI-exposed rats repeated intrathecal PD98059 (2.5 mcg) administration produced after 30 min a strong anti-allodynic effect (20.5 g ± 1.0, n = 10) as measured on day seven compared to vehicle-treated animals (13.08 g ± 0.5, n = 10; Fig 4A). Single injection of morphine attenuated on allodynia (20.1 g ± 0.8, n = 10, Fig 4A). Repeated intrathecal PD98059 (2.5 mcg) administration improved the response to morphine (24.8 ± 0.7, n = 7, Fig 4A).


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 opioid analgesia in a naive and neuropathic rats.Effect of repeated vehicle or PD98059 administration (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the analgesic effects of a single injection of morphine (5 mcg/5 mcl; i.t.) in CCI-exposed rats on day 7 after injury as measured by von Frey (A) and cold plate (B) in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (C, 2.5 mcg/5 mcl) and buprenorphine (D, 2.5 mcg/5 mcl) as measured by von Frey in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (E, 0.5 mcg/5 mcl) and buprenorphine (F, 2.5 mcg/5 mcl) as measured by tail flick test in naive animals. Behavioral tests were conducted 30 min after vehicle or PD98059 administration and then 30 min after a single vehicle, morphine or buprenorphine injection. Data are presented as the means ± SEM. The inter-group differences were analyzed using ANOVA and Bonferroni’s multiple comparison test. ###p<0.001 indicates a significant difference compared to the control group; $ $p<0.01 and $ $ $p<0.001 indicate significant differences compared to the repeated or single PD-treated CCI-exposed rats which received single morphine or buprenorphine injection, and °p<0.05, and °°°p<0.001 indicate significant differences between repeated or single PD-treated CCI-exposed or naive rats to repeated or single PD-treated CCI-exposed or naive rats which received single morphine or buprenorphine C, control; V, vehicle; PD, PD98059. The number of animals per group—Figs A&B: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 10, PD+M-CCI n = 7; Fig C: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 8; Fig D: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 7; Fig E: V+V-CCI n = 12; PD+V-CCI n = 10, V+M-CCI n = 7, PD+M-CCI n = 6; Fig F: V+V-CCI n = 8; PD+V-CCI n = 12, V+B-CCI n = 6, PD+B-CCI n = 6.
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pone.0138583.g004: Effect of PD98059 on opioid analgesia in a naive and neuropathic rats.Effect of repeated vehicle or PD98059 administration (2.5 mcg/5 mcl; i.t.; 16 h and 1 h before CCI and then once daily for 7 days) on the analgesic effects of a single injection of morphine (5 mcg/5 mcl; i.t.) in CCI-exposed rats on day 7 after injury as measured by von Frey (A) and cold plate (B) in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (C, 2.5 mcg/5 mcl) and buprenorphine (D, 2.5 mcg/5 mcl) as measured by von Frey in neuropathic animals. Effect of a single administration of vehicle or PD98059 (2.5 mcg/5 mcl) on a single i.t. injection of morphine (E, 0.5 mcg/5 mcl) and buprenorphine (F, 2.5 mcg/5 mcl) as measured by tail flick test in naive animals. Behavioral tests were conducted 30 min after vehicle or PD98059 administration and then 30 min after a single vehicle, morphine or buprenorphine injection. Data are presented as the means ± SEM. The inter-group differences were analyzed using ANOVA and Bonferroni’s multiple comparison test. ###p<0.001 indicates a significant difference compared to the control group; $ $p<0.01 and $ $ $p<0.001 indicate significant differences compared to the repeated or single PD-treated CCI-exposed rats which received single morphine or buprenorphine injection, and °p<0.05, and °°°p<0.001 indicate significant differences between repeated or single PD-treated CCI-exposed or naive rats to repeated or single PD-treated CCI-exposed or naive rats which received single morphine or buprenorphine C, control; V, vehicle; PD, PD98059. The number of animals per group—Figs A&B: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 10, PD+M-CCI n = 7; Fig C: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 8; Fig D: V+V-CCI n = 10; PD+V-CCI n = 10, V+M-CCI n = 8, PD+M-CCI n = 7; Fig E: V+V-CCI n = 12; PD+V-CCI n = 10, V+M-CCI n = 7, PD+M-CCI n = 6; Fig F: V+V-CCI n = 8; PD+V-CCI n = 12, V+B-CCI n = 6, PD+B-CCI n = 6.
Mentions: In CCI-exposed rats repeated intrathecal PD98059 (2.5 mcg) administration produced after 30 min a strong anti-allodynic effect (20.5 g ± 1.0, n = 10) as measured on day seven compared to vehicle-treated animals (13.08 g ± 0.5, n = 10; Fig 4A). Single injection of morphine attenuated on allodynia (20.1 g ± 0.8, n = 10, Fig 4A). Repeated intrathecal PD98059 (2.5 mcg) administration improved the response to morphine (24.8 ± 0.7, n = 7, Fig 4A).

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