11 research outputs found
New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding
Anandamide suppressess pain initiation through a peripheral endocannabinoid mechanism
none15sìPeripheral 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.restrictedCLAPPER JR; MORENO-SANZ G; RUSSO R; GUIJARRO A; VACONDIO F; DURANTI A; TONTINI A; SANCHINI S; SCIOLINO NR; SPRADLEY JM; HOHMANN AG; CALIGNANO A; MOR M; TARZIA G; PIOMELLI DClapper, Jr; MORENO SANZ, G; Russo, R; Guijarro, A; Vacondio, F; Duranti, Andrea; Tontini, Andrea; Sanchini, Silvano; Sciolino, Nr; Spradley, Jm; Hohmann, Ag; Calignano, A; Mor, M; Tarzia, Giorgio; Piomelli, D