Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism

The authors have developed a new inhibitor of the enzyme that degrades the endocannabinoid anandamide. This new drug does not cross the blood-brain barrier. It elevates peripheral anandamide only, which, acting on peripheral CB1 receptors, attenuates pain responses in rodents. 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. CB 1 cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB 1 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.