The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy.
OBJECTIVE
Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB(1)) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects.


METHODS
The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain.


RESULTS
Systemically administered L-29 (10 mg kg(-1)) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg(-1)). The CB(1) receptor antagonist SR141716a (1 mg kg(-1)) and the CB(2) receptor antagonist SR144528 (1 mg kg(-1)) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-alpha antagonist, MK-886 (1 mg kg(-1)), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg(-1)) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity.


CONCLUSIONS
L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation.
Wallace
V C J
VC
Pain Research Group, Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London, UK.
Segerdahl
A R
AR
Lambert
D M
DM
Vandevoorde
S
S
Blackbeard
J
J
Pheby
T
T
Hasnie
F
F
Rice
A S C
AS
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000588:Amines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001892:Camphanes / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004983:Ethanolamines; D000077206:Gabapentin; D006614:Hindlimb; D007211:Indoles / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D047493:PPAR alpha / Q000037:antagonists & inhibitors; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010169:Palmitic Acids / Q000737:chemistry / Q000494:pharmacology*; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D020426:Sciatic Neuropathy / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D013696:Temperature; D016047:Zalcitabine / Q000008:administration & dosage / Q000633:toxicity; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D002722:Chlorobenzenes
D000577:Amides; D000588:Amines; D001892:Camphanes; D003509:Cyclohexanecarboxylic Acids; D063388:Endocannabinoids; D004983:Ethanolamines; D000077206:Gabapentin; D007211:Indoles; D047493:PPAR alpha; D010169:Palmitic Acids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000077285:Rimonabant; D016047:Zalcitabine; D005680:gamma-Aminobutyric Acid; C110630:SR 144528; C060893:MK-886; D002722:Chlorobenzenes; C005958:palmidrol