title: 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.affiliation: Program in Neuroscience, Indiana University, Bloomington, IN, USA.
authors.forename: Liting
authors.initials: L
authors.lastname: Deng
authors.forename: Josée
authors.initials: J
authors.lastname: Guindon
authors.forename: V Kiran
authors.initials: VK
authors.lastname: Vemuri
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Hohmann
mesh_terms: D000818:Animals; D001596:Benzylamines; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D000080027:Cyclams; D004195:Disease Models, Animal; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017239:Paclitaxel / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C500321:3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one; D001596:Benzylamines; D002867:Chromones; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007211:Indoles; D010880:Piperidines; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D019718:Receptors, CXCR4; C103505:AM 251; D017239:Paclitaxel; D002945:Cisplatin; C088327:plerixafor; C094023:iodopravadoline