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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / deficiency
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Amidohydrolases / metabolism
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Animals
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Arachidonic Acids / metabolism*
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Arachidonic Acids / therapeutic use*
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Cannabinoid Receptor Modulators / antagonists & inhibitors
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Cannabinoid Receptor Modulators / metabolism*
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Cannabinoid Receptor Modulators / therapeutic use*
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Cannabinoids / pharmacology
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Cannabinoids / therapeutic use
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Carrageenan
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Chromatography, Liquid / methods
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Disease Models, Animal
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Drug Administration Routes
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Drug Administration Schedule
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Endocannabinoids*
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Enzyme Inhibitors
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Escape Reaction / drug effects
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Ethylene Glycols / metabolism
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Feeding Behavior / drug effects
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Formaldehyde
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Hyperalgesia / drug therapy
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Hyperalgesia / genetics
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Indoles / therapeutic use
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Male
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Mass Spectrometry / methods
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monoacylglycerol Lipases / metabolism
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Motor Activity / drug effects
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Oncogene Proteins v-fos / metabolism
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PPAR alpha / deficiency
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Pain / chemically induced
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Pain / genetics
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Pain / pathology
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Pain / prevention & control*
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Pain Measurement / drug effects
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Pain Threshold / drug effects
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Peripheral Nervous System Diseases
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Piperidines / therapeutic use
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Polyunsaturated Alkamides / metabolism*
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Polyunsaturated Alkamides / therapeutic use*
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Pyrazoles / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Rimonabant
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Sciatica / drug therapy
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Spinal Cord / metabolism
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Statistics, Nonparametric
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Time Factors
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Tissue Distribution / drug effects
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Tritium
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Cannabinoids
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Endocannabinoids
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Enzyme Inhibitors
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Ethylene Glycols
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Indoles
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Oncogene Proteins v-fos
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PPAR alpha
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Piperidines
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Polyunsaturated Alkamides
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Pyrazoles
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URB937
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arachidonoylethylene glycol
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MK-886
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Tritium
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Formaldehyde
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Carrageenan
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Monoacylglycerol Lipases
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Amidohydrolases
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fatty-acid amide hydrolase
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Rimonabant
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iodopravadoline
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anandamide