Continuous infusion of the cannabinoid WIN 55,212-2 to the site of a peripheral nerve injury reduces mechanical and cold hypersensitivity.
OBJECTIVE
Cannabinoids have analgesic and anti-inflammatory properties but their use is limited by psychotropic activity at CNS receptors. Restricting cannabinoid delivery to peripheral tissues at systemically inactive doses offers a potential solution to this problem.


METHODS
WIN 55,212-2 was continuously delivered to the site of a partial ligation injury to the sciatic nerve via a perineural catheter connected to a mini-osmotic pump implanted at the time of injury. Bilateral reflex limb withdrawal behaviour was measured in adult male Wistar rats in response to mechanical and cooling stimulation of the hind paw.


RESULTS
Compared with vehicle treatment, WIN 55,212-2 (1.4 microg microl(-1) hr(-1)) reduced hypersensitivity to stimuli applied to the injured limb at 2, 4 and 6 days after injury. The effects of WIN 55,212-2 (0.6-2.8 microg microl(-1) hr(-1)) were dose-dependent. Estimated EC(50) values for reduction in mean responses to mechanical and cooling stimulation (day 4 post-surgery) were 1.55 (95% C.I, [1.11-2.16]) microg microl(-1) hr(-1) and 1.52 (95% C.I, [1.07-2.18]) microg microl(-1) hr(-1), respectively. When delivered to the contralateral side to injury, WIN 55,212-2 (1.4 or 2.8 microg microl(-1) hr(-1)) did not significantly affect nerve injury-associated hypersensitivity. Co-perineural application of a CB(1) receptor antagonist SR141716a and WIN 55,212-2 prevented the effects of WIN 55,212-2 on hypersensitivity. Co-application of CB(2) receptor antagonist SR144528 reversed WIN 55,212-2's effect on mechanical hypersensitivity on day 2 only.


CONCLUSIONS
These data support a peripheral antihyperalgesic effect of WIN 55,212-2 when delivered directly to the site of a nerve injury at systemically inactive doses.
Lever
I J
IJ
Department of Anaesthetics, Intensive Care and Pain Medicine, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK.
Pheby
T M
TM
Rice
A S C
AS
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology*; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D007260:Infusion Pumps; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D010812:Physical Stimulation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D012584:Sciatic Nerve / Q000293:injuries*; D013697:Thermosensing / Q000187:drug effects; D013997:Time Factors
D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant