The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy
<p>Abstract</p> <p>Background</p> <p>Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB<sub>2</sub> agonist, produces antinociception wit...
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2012-09-01
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| Series: | Molecular Pain |
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| Online Access: | http://www.molecularpain.com/content/8/1/71 |
| _version_ | 1819182502307168256 |
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| author | Deng Liting Guindon Josée Vemuri V Thakur Ganesh A White Fletcher A Makriyannis Alexandros Hohmann Andrea G |
| author_facet | Deng Liting Guindon Josée Vemuri V Thakur Ganesh A White Fletcher A Makriyannis Alexandros Hohmann Andrea G |
| author_sort | Deng Liting |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB<sub>2</sub> agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB<sub>2</sub> agonist efficacy.</p> <p>Results</p> <p>AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB<sub>2</sub> antagonist AM630 (3 mg/kg i.p.), but not the CB<sub>1</sub> antagonist AM251 (3 mg/kg i.p.), consistent with a CB<sub>2</sub>-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action.</p> <p>Conclusions</p> <p>Our results indicate that activation of cannabinoid CB<sub>2</sub> receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB<sub>2</sub> receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.</p> |
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| institution | Directory Open Access Journal |
| issn | 1744-8069 |
| language | English |
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| publishDate | 2012-09-01 |
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| spelling | doaj.art-0b924f2712c54ec88a9de4c5022613ab2022-12-21T18:10:03ZengSAGE PublishingMolecular Pain1744-80692012-09-01817110.1186/1744-8069-8-71The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathyDeng LitingGuindon JoséeVemuri VThakur Ganesh AWhite Fletcher AMakriyannis AlexandrosHohmann Andrea G<p>Abstract</p> <p>Background</p> <p>Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB<sub>2</sub> agonist, produces antinociception without producing central nervous system (CNS)-associated side effects. The present study was conducted to examine the antinociceptive effect of AM1710 in rodent models of neuropathic pain evoked by diverse chemotherapeutic agents (cisplatin and paclitaxel). A secondary objective was to investigate the potential contribution of alpha-chemokine receptor (CXCR4) signaling to both chemotherapy-induced neuropathy and CB<sub>2</sub> agonist efficacy.</p> <p>Results</p> <p>AM1710 (0.1, 1 or 5 mg/kg i.p.) suppressed the maintenance of mechanical and cold allodynia in the cisplatin and paclitaxel models. Anti-allodynic effects of AM1710 were blocked by the CB<sub>2</sub> antagonist AM630 (3 mg/kg i.p.), but not the CB<sub>1</sub> antagonist AM251 (3 mg/kg i.p.), consistent with a CB<sub>2</sub>-mediated effect. By contrast, blockade of CXCR4 signaling with its receptor antagonist AMD3100 (10 mg/kg i.p.) failed to attenuate mechanical or cold hypersensitivity induced by either cisplatin or paclitaxel. Moreover, blockade of CXCR4 signaling failed to alter the anti-allodynic effects of AM1710 in the paclitaxel model, further suggesting distinct mechanisms of action.</p> <p>Conclusions</p> <p>Our results indicate that activation of cannabinoid CB<sub>2</sub> receptors by AM1710 suppresses both mechanical and cold allodynia in two distinct models of chemotherapy-induced neuropathic pain. By contrast, CXCR4 signaling does not contribute to the maintenance of chemotherapy-induced established neuropathy or efficacy of AM1710. Our studies suggest that CB<sub>2</sub> receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.</p>http://www.molecularpain.com/content/8/1/71EndocannabinoidCannabilactoneAM1710ChemotherapyNeuropathic painChemokineCXCR4Mechanical allodyniaCold allodyniaHyperalgesia |
| spellingShingle | Deng Liting Guindon Josée Vemuri V Thakur Ganesh A White Fletcher A Makriyannis Alexandros Hohmann Andrea G The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy Molecular Pain Endocannabinoid Cannabilactone AM1710 Chemotherapy Neuropathic pain Chemokine CXCR4 Mechanical allodynia Cold allodynia Hyperalgesia |
| title | The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy |
| title_full | The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy |
| title_fullStr | The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy |
| title_full_unstemmed | The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy |
| title_short | The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB<sub>2</sub> receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy |
| title_sort | maintenance of cisplatin and paclitaxel induced mechanical and cold allodynia is suppressed by cannabinoid cb sub 2 sub receptor activation and independent of cxcr4 signaling in models of chemotherapy induced peripheral neuropathy |
| topic | Endocannabinoid Cannabilactone AM1710 Chemotherapy Neuropathic pain Chemokine CXCR4 Mechanical allodynia Cold allodynia Hyperalgesia |
| url | http://www.molecularpain.com/content/8/1/71 |
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