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.
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We thank E. Dotsey for help with experiments. This research was supported by grants from the National Institutes on Drug Abuse (D.P. and A.G.H.), the University of Parma (M.M.) and the Italian Ministry for Public Education, University and Research (G.T., A.D and A.T.). G.M.-S. was partially supported by the Fulbright Commission and the Exchange Abroad Program, University of California. The support of the Agilent Foundation is gratefully acknowledged.
A patent application covering URB937 and allied compounds has been filed on behalf of the inventors (D.P., J.R.C., G.M.-S., A.D., A.T., M.M. and G.T.) by the University of California, Irvine, the Italian Institute of Technology, and the Universities of Urbino and Parma.
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