Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism.
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.
Clapper
Jason R
JR
Department of Pharmacology, University of California Irvine, Irvine, California, USA.
Moreno-Sanz
Guillermo
G
Russo
Roberto
R
Guijarro
Ana
A
Vacondio
Federica
F
Duranti
Andrea
A
Tontini
Andrea
A
Sanchini
Silvano
S
Sciolino
Natale R
NR
Spradley
Jessica M
JM
Hohmann
Andrea G
AG
Calignano
Antonio
A
Mor
Marco
M
Tarzia
Giorgio
G
Piomelli
Daniele
D
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
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