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

Molecular Pain

Andrea G Hohmann²  Alexandros Makriyannis³  Fletcher A White¹  Ganesh A Thakur³  V Kiran Vemuri³  Josée Guindon²  Liting Deng⁴ 

[1] Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA;Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, MA, USA;Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, IN, USA

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

Others  :  863363
DOI  :  10.1186/1744-8069-8-71

 received in 2012-05-30, accepted in 2012-09-19,  发布年份 2012

【 摘 要 】

Background

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.

Results

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.

Conclusions

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.

【 授权许可】

   
2012 Deng et al.; licensee BioMed Central Ltd.

【 图 表 】

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