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The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB2 receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy

Liting Deng123, Josée Guindon4, V Kiran Vemuri5, Ganesh A Thakur5, Fletcher A White6, Alexandros Makriyannis5 and Andrea G Hohmann134*

Author Affiliations

1 Program in Neuroscience, Indiana University, Bloomington, IN, USA

2 Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USA

3 Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, IN, USA

4 Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

5 Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA

6 Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA

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Molecular Pain 2012, 8:71  doi:10.1186/1744-8069-8-71

Published: 22 September 2012



Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone CB2 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 CB2 agonist efficacy.


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 CB2 antagonist AM630 (3 mg/kg i.p.), but not the CB1 antagonist AM251 (3 mg/kg i.p.), consistent with a CB2-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.


Our results indicate that activation of cannabinoid CB2 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 CB2 receptors represent a promising therapeutic target for the treatment of toxic neuropathies produced by cisplatin and paclitaxel chemotherapeutic agents.

Endocannabinoid; Cannabilactone; AM1710; Chemotherapy; Neuropathic pain; Chemokine; CXCR4; Mechanical allodynia; Cold allodynia; Hyperalgesia