Inhibition of Ca 2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats

Masafumi Shirahama, Soichiro Ushio, Nobuaki Egashira, Shota Yamamoto, Hikaru Sada, Ken Masuguchi, takehiro kawashiri, Ryozo Oishi

研究成果: ジャーナルへの寄稿記事

22 引用 (Scopus)

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Background: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl- D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca 2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca 2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.Results: An increase of CaMKII phosphorylation was found in the spinal cord (L 4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.Conclusions: These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.

元の言語英語
記事番号26
ジャーナルMolecular Pain
8
DOI
出版物ステータス出版済み - 4 17 2012

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oxaliplatin
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Hyperalgesia
Trifluoperazine
Phosphorylation
Peripheral Nervous System Diseases
Spinal Injections

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine

これを引用

Inhibition of Ca 2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats. / Shirahama, Masafumi; Ushio, Soichiro; Egashira, Nobuaki; Yamamoto, Shota; Sada, Hikaru; Masuguchi, Ken; kawashiri, takehiro; Oishi, Ryozo.

:: Molecular Pain, 巻 8, 26, 17.04.2012.

研究成果: ジャーナルへの寄稿記事

Shirahama, Masafumi ; Ushio, Soichiro ; Egashira, Nobuaki ; Yamamoto, Shota ; Sada, Hikaru ; Masuguchi, Ken ; kawashiri, takehiro ; Oishi, Ryozo. / Inhibition of Ca 2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats. :: Molecular Pain. 2012 ; 巻 8.
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title = "Inhibition of Ca 2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats",
abstract = "Background: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl- D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca 2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca 2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.Results: An increase of CaMKII phosphorylation was found in the spinal cord (L 4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.Conclusions: These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.",
author = "Masafumi Shirahama and Soichiro Ushio and Nobuaki Egashira and Shota Yamamoto and Hikaru Sada and Ken Masuguchi and takehiro kawashiri and Ryozo Oishi",
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T1 - Inhibition of Ca 2+/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats

AU - Shirahama, Masafumi

AU - Ushio, Soichiro

AU - Egashira, Nobuaki

AU - Yamamoto, Shota

AU - Sada, Hikaru

AU - Masuguchi, Ken

AU - kawashiri, takehiro

AU - Oishi, Ryozo

PY - 2012/4/17

Y1 - 2012/4/17

N2 - Background: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl- D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca 2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca 2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.Results: An increase of CaMKII phosphorylation was found in the spinal cord (L 4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.Conclusions: These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.

AB - Background: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl- D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca 2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca 2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.Results: An increase of CaMKII phosphorylation was found in the spinal cord (L 4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.Conclusions: These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.

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