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


METHODS
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).


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
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.
Rahn
E J
EJ
Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA 30602-3013, USA.
Makriyannis
A
A
Hohmann
A G
AG
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb; D006941:Hyperesthesia / Q000139:chemically induced / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009437:Neuralgia / Q000139:chemically induced / Q000517:prevention & control*; D010147:Pain Measurement / Q000295:instrumentation / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology*; D000077285:Rimonabant; D013697:Thermosensing / Q000502:physiology; D014750:Vincristine / Q000008:administration & dosage / Q000633:toxicity*
C439263:AM 1241; D048588:Benzoxazines; D001892:Camphanes; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D014750:Vincristine; D009020:Morphine; D000077285:Rimonabant