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.

Abstract

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.

• Authors: Liting Deng, Josée Guindon, V Kiran Vemuri, Ganesh A Thakur, Fletcher A White, Alexandros Makriyannis, Andrea G Hohmann
• Journal: Molecular pain (Mol Pain) Vol. 8 Pg. 71 (Sep 22 2012) ISSN: 1744-8069 [Electronic] United States
• PMID: 22998838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one
• Benzylamines
• Chromones
• Cyclams
• Heterocyclic Compounds
• Indoles
• Piperidines
• Pyrazoles
• Receptor, Cannabinoid, CB2
• Receptors, CXCR4
• AM 251
• Paclitaxel
• Cisplatin
• plerixafor
• iodopravadoline

Topics

• Animals
• Benzylamines
• Chromones (chemistry, pharmacology, therapeutic use)
• Cisplatin (adverse effects)
• Cryopyrin-Associated Periodic Syndromes (chemically induced, complications, drug therapy, metabolism)
• Cyclams
• Disease Models, Animal
• Heterocyclic Compounds (chemistry, pharmacology, therapeutic use)
• Hyperalgesia (chemically induced, complications, drug therapy, metabolism)
• Indoles (chemistry, pharmacology, therapeutic use)
• Male
• Paclitaxel (adverse effects)
• Peripheral Nervous System Diseases (chemically induced, complications, drug therapy, metabolism)
• Piperidines (chemistry, pharmacology, therapeutic use)
• Pyrazoles (chemistry, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB2 (agonists, antagonists & inhibitors, metabolism)
• Receptors, CXCR4 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Treatment Outcome