l-663536 and Pain

Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB₁ cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB₁ receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Carrageenan; Chromatography, Liquid; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Endocannabinoids; Enzyme Inhibitors; Escape Reaction; Ethylene Glycols; Feeding Behavior; Formaldehyde; Gene Expression Regulation; Hyperalgesia; Indoles; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Motor Activity; Oncogene Proteins v-fos; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Piperidines; Polyunsaturated Alkamides; PPAR alpha; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Sciatica; Spinal Cord; Statistics, Nonparametric; Time Factors; Tissue Distribution; Tritium

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Fever; Humans; Intramolecular Oxidoreductases; Mice; Mice, Knockout; Microsomes; Pain; Prostaglandin-E Synthases; Stroke

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

Topics: Amides; Amines; Animals; Behavior, Animal; Camphanes; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Endocannabinoids; Ethanolamines; Gabapentin; gamma-Aminobutyric Acid; Hindlimb; Indoles; Injections, Intraperitoneal; Male; Pain; Pain Measurement; Pain Threshold; Palmitic Acids; Physical Stimulation; Piperidines; PPAR alpha; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Sciatic Neuropathy; Temperature; Zalcitabine