Analgesics exogenous

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

Similar to exogenous cannabinoids, anandamide has analgesic effects (Fride and Mechoulam 1993). Peripheral anandamide (10 mg/kg IM) produces antinociception in primates. However, centrally administered anandamide does not alter pain perceptive thresholds (Murillo-... 

Animal and human clinical studies demonstrate that both endogenous and exogenous opioids can also produce opioid-mediated analgesia at sites outside the CNS. Pain associated with inflammation seems especially sensitive to these peripheral opioid actions. The identification of functional p receptors on the peripheral terminals of sensory neurons supports this hypothesis. Furthermore, activation of peripheral preceptors results in a decrease in sensory neuron activity and transmitter release. Peripheral administration of opioids, eg, into the knees of patients undergoing arthroscopic knee surgery, has shown some clinical benefit. If they can be developed, opioids selective for a peripheral site would be useful adjuncts in the treatment of inflammatory pain (see Ion Channels Novel Analgesics). Moreover, new peripherally acting dynorphins may provide a novel means to treat visceral pain. 

Finally, transgenic FAAH-deficient mice have been developed. They are more responsive to exogenously administered AEA (Cravatt et al. 2001), and their brains contain 15-fold higher levels of AEA than wild-type mice. The phenotype of these mice is characterized also by higher susceptibility to kainate-induced seizures (Clement et al. 2003) and by lower sensitivity to some painful stimuli (Cravatt et al. 2001), which suggests that inhibition of FAAH might lead to the development of novel analgesics. 

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