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

Mol Pain. 2012 Sep 22;8:71. doi: 10.1186/1744-8069-8-71.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chromones / chemistry
  • Chromones / pharmacology
  • Chromones / therapeutic use
  • Cisplatin / adverse effects*
  • Cryopyrin-Associated Periodic Syndromes / chemically induced*
  • Cryopyrin-Associated Periodic Syndromes / complications
  • Cryopyrin-Associated Periodic Syndromes / drug therapy
  • Cryopyrin-Associated Periodic Syndromes / metabolism
  • Disease Models, Animal
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Heterocyclic Compounds / therapeutic use
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / complications
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Indoles / chemistry
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Male
  • Paclitaxel / adverse effects*
  • 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

Substances

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

Supplementary concepts

  • Cold Hypersensitivity