Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats

Background and purpose: The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified. Experimental approach: Mechanical hypersensitivity...

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Published in:British journal of pharmacology 2007-11, Vol.152 (5), p.765-777
Main Authors: Rahn, E J, Makriyannis, A, Hohmann, A G
Format: Article
Language:English
Subjects:
allodynia
Animals
Benzoxazines - pharmacology
Body Weight - drug effects
Camphanes - pharmacology
cancer
cannabinoid
Cannabinoids - pharmacology
Catalepsy - chemically induced
Catalepsy - prevention & control
CB1
CB2
chemotherapy
Dose-Response Relationship, Drug
Hindlimb
hyperalgesia
Hyperesthesia - chemically induced
Hyperesthesia - prevention & control
Injections, Intraperitoneal
Injections, Spinal
Male
Morphine - pharmacology
Morpholines - pharmacology
Naphthalenes - pharmacology
Neuralgia - chemically induced
Neuralgia - prevention & control
neuropathic pain
Pain Measurement - instrumentation
Pain Measurement - methods
Pain Threshold - drug effects
Physical Stimulation
Piperidines - pharmacology
Pyrazoles - pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1 - agonists
Receptor, Cannabinoid, CB1 - physiology
Receptor, Cannabinoid, CB2 - agonists
Receptor, Cannabinoid, CB2 - physiology
Research Papers
Rimonabant
Thermosensing - physiology
Vincristine - administration & dosage
Vincristine - toxicity
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Summary:Background and purpose: The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified. Experimental approach: Mechanical hypersensitivity developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same times. Effects of the CB1/CB2 receptor agonist WIN55,212‐2, the receptor‐inactive enantiomer WIN55,212‐3, the CB2‐selective agonist (R,S)‐AM1241, the opiate agonist morphine and vehicle on chemotherapy‐induced neuropathy were evaluated. WIN55,212‐2 was administered intrathecally (i.t.) or locally in the hindpaw to identify sites of action. Pharmacological specificity was established using competitive antagonists for CB1 (SR141716) or CB2 receptors (SR144528). Key results: Systemic administration of WIN55,212‐2, but not WIN55,212‐3, suppressed vincristine‐evoked mechanical allodynia. A leftward shift in the dose‐response curve was observed following WIN55,212‐2 relative to morphine treatment. The CB1 (SR141716) and CB2 (SR144528) antagonists blocked the anti‐allodynic effects of WIN55,212‐2. (R,S)‐AM1241 suppressed vincristine‐induced mechanical hypersensitivity through a CB2 mechanism. Both cannabinoid agonists suppressed vincristine‐induced mechanical hypersensitivity without inducing catalepsy. Spinal sites of action are implicated in cannabinoid modulation of chemotherapy‐induced neuropathy. WIN55,212‐2, but not WIN55,212‐3, administered i.t. suppressed vincristine‐evoked mechanical hypersensitivity at doses that were inactive following local hindpaw administration. Spinal coadministration of both the CB1 and CB2 antagonists blocked the anti‐allodynic effects of WIN55,212‐2. Conclusions and implications: Cannabinoids suppress the maintenance of vincristine‐induced mechanical allodynia through activation of CB1 and CB2 receptors. These anti‐allodynic effects are mediated, at least in part, at the level of the spinal cord. British Journal of Pharmacology (2007) 152, 765–777; doi:10.1038/sj.bjp.0707333; published online 18 June 2007
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0707333