Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats
<p>Abstract</p> <p>Background</p> <p>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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2012-04-01
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| Series: | Molecular Pain |
| Online Access: | http://www.molecularpain.com/content/8/1/26 |
| _version_ | 1828359101595254784 |
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| author | Shirahama Masafumi Ushio Soichiro Egashira Nobuaki Yamamoto Shota Sada Hikaru Masuguchi Ken Kawashiri Takehiro Oishi Ryozo |
| author_facet | Shirahama Masafumi Ushio Soichiro Egashira Nobuaki Yamamoto Shota Sada Hikaru Masuguchi Ken Kawashiri Takehiro Oishi Ryozo |
| author_sort | Shirahama Masafumi |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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 <it>N</it>-methyl-<sub>D</sub>-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca<sup>2+</sup>/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca<sup>2+ </sup>influx, in the oxaliplatin-induced mechanical allodynia in rats.</p> <p>Results</p> <p>An increase of CaMKII phosphorylation was found in the spinal cord (L<sub>4-6</sub>) 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.</p> <p>Conclusions</p> <p>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.</p> |
| first_indexed | 2024-04-14T03:37:52Z |
| format | Article |
| id | doaj.art-ab3e8685424e4a71a01db85ac768a6ad |
| institution | Directory Open Access Journal |
| issn | 1744-8069 |
| language | English |
| last_indexed | 2024-04-14T03:37:52Z |
| publishDate | 2012-04-01 |
| publisher | SAGE Publishing |
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| series | Molecular Pain |
| spelling | doaj.art-ab3e8685424e4a71a01db85ac768a6ad2022-12-22T02:14:41ZengSAGE PublishingMolecular Pain1744-80692012-04-01812610.1186/1744-8069-8-26Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in RatsShirahama MasafumiUshio SoichiroEgashira NobuakiYamamoto ShotaSada HikaruMasuguchi KenKawashiri TakehiroOishi Ryozo<p>Abstract</p> <p>Background</p> <p>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 <it>N</it>-methyl-<sub>D</sub>-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca<sup>2+</sup>/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca<sup>2+ </sup>influx, in the oxaliplatin-induced mechanical allodynia in rats.</p> <p>Results</p> <p>An increase of CaMKII phosphorylation was found in the spinal cord (L<sub>4-6</sub>) 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.</p> <p>Conclusions</p> <p>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.</p>http://www.molecularpain.com/content/8/1/26 |
| spellingShingle | Shirahama Masafumi Ushio Soichiro Egashira Nobuaki Yamamoto Shota Sada Hikaru Masuguchi Ken Kawashiri Takehiro Oishi Ryozo Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats Molecular Pain |
| title | Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats |
| title_full | Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats |
| title_fullStr | Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats |
| title_full_unstemmed | Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats |
| title_short | Inhibition of Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II reverses oxaliplatin-induced mechanical allodynia in Rats |
| title_sort | inhibition of ca sup 2 sup calmodulin dependent protein kinase ii reverses oxaliplatin induced mechanical allodynia in rats |
| url | http://www.molecularpain.com/content/8/1/26 |
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