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

• Published in: Molecular pain Vol. 8; no. 1; p. 71
• Main Authors: Deng, Liting, Guindon, Josée, Vemuri, V Kiran, Thakur, Ganesh A, White, Fletcher A, Makriyannis, Alexandros, Hohmann, Andrea G
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 22.09.2012; BioMed Central Ltd; Sage Publications Ltd; BioMed Central; SAGE Publishing
• Subjects: AM1710; Animals; Antimitotic agents; Antineoplastic agents; Behavior; Cancer; Cannabilactone; Chemokine; Chemokines; Chemotherapy; Chromones - chemistry; Chromones - pharmacology; Chromones - therapeutic use; Cisplatin - adverse effects; Cold; Cold allodynia; Cryopyrin-Associated Periodic Syndromes - chemically induced; Cryopyrin-Associated Periodic Syndromes - complications; Cryopyrin-Associated Periodic Syndromes - drug therapy; Cryopyrin-Associated Periodic Syndromes - metabolism; CXCR4; Disease Models, Animal; Drug dosages; Endocannabinoid; Health sciences; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Heterocyclic Compounds - therapeutic use; HIV; Human immunodeficiency virus; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - complications; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Male; Mechanical allodynia; Neuropathic pain; Paclitaxel - adverse effects; Pain; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - complications; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - metabolism; Piperidines - chemistry; Piperidines - pharmacology; Piperidines - therapeutic use; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Receptors, CXCR4 - antagonists & inhibitors; Receptors, CXCR4 - metabolism; Signal Transduction - drug effects; Time Factors; Treatment Outcome; Chemokine; Chemotherapy; Endocannabinoid; Cold allodynia; CXCR4; Cannabilactone; AM1710; Neuropathic pain; Mechanical allodynia; Hyperalgesia
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1186/1744-8069-8-71

Background: Chemotherapeutic agents produce dose-limiting peripheral neuropathy through mechanisms that remain poorly understood. We previously showed that AM1710, a cannabilactone 2 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.