The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1

Abstract

Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory 'load'. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs.

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

“…These findings, coupled with the synergistic antinociceptive interactions between the NSAIDs and FAAH inhibition (Fowler et al, 2009;Naidu et al, 2009), support the idea that FAAH and MAGL are promising targets for the development of analgesic therapeutics that not only lack adverse gastrointestinal side effects, but also protect against NSAID-induced gastric ulcers.…”

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

“…Although DAGLα −/− and DAGLβ −/− mice have provided valuable models for investigating the in vivo effects of disrupting endocannabinoid biosynthesis, DAGLα plays an important role in brain development (13) and chronic alterations in endocannabinoid tone can lead to substantial CB 1 R adaptations in the CNS (45,46) and peripheral tissues (47). The endocannabinoid system also crosstalks with several other bioactive lipid pathways (8,48,49). The extent to which this larger lipid network is dynamically regulated in the CNS by acute disruption of endocannabinoid synthesis remains unknown.…”

Ibuprofen: pharmacology, efficacy and safety

“…There may be some contribution of inhibition of COX-1 in the CNS to the analgesic actions of ibuprofen (Martínez et al 2002). Recently, much interest has been shown in the possibility that ibuprofen may enhance the synthesis of endogenous cannabinoids and so contribute to the central analgesia via cannabinoid receptor activation (Fowler et al 2009) as well as acting on NMDA receptors (Björkman et al 1996). There is possibly a contribution of R(-) ibuprofen to the effects on both the leucocyte activation neural activity and spinal transmission influencing the effects of ibuprofen in inflammatory pain.…”