title: Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of California Irvine, Irvine, California, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Clapper
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Ana
authors.initials: A
authors.lastname: Guijarro
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Silvano
authors.initials: S
authors.lastname: Sanchini
authors.forename: Natale R
authors.initials: NR
authors.lastname: Sciolino
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Spradley
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Hohmann
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000627:therapeutic use*; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use*; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002351:Carrageenan; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004924:Escape Reaction / Q000187:drug effects; D005026:Ethylene Glycols / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005557:Formaldehyde; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D047493:PPAR alpha / Q000172:deficiency; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases; D010880:Piperidines / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000378:metabolism* / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D012585:Sciatica / Q000188:drug therapy; D013116:Spinal Cord / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases; D002722:Chlorobenzenes
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D002351:Carrageenan; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005026:Ethylene Glycols; D005557:Formaldehyde; D007211:Indoles; D008994:Monoacylglycerol Lipases; D016761:Oncogene Proteins v-fos; D047493:PPAR alpha; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D000077285:Rimonabant; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases; C552918:URB937; C114008:arachidonoylethylene glycol; C060893:MK-886; D002722:Chlorobenzenes; C094023:iodopravadoline; C078814:anandamide