Peripheral FAAH as a target for novel analgesics

DESCRIPTION (provided by applicant): Pain management remains a significant unmet medical need. Anandamide is an endogenous marijuana-like ('endocannabinoid') molecule that plays important roles in the regulation of pain. Previous work has shown that endocannabinoid receptors located outside the central nervous system (CNS) exert a powerful regulatory control over pain initiation. Moreover, there is evidence that clinical conditions associated with chronic pain are accompanied by abnormal elevations in the peripheral levels of anandamide. The biological actions of anandamide are stopped by the intracellular enzyme, fatty acid amide hydrolase (FAAH), which catalyzes the deactivating hydrolysis of anandamide. To explore the role of peripheral anandamide in painregulation, the lab of Daniele Piomelli at the University of California, Irvine, has developed a novel class of FAAH inhibitors that do not enter the CNS and therefore suppress anandamide deactivation only in the periphery of the body. The prototype member of this class is called URB937. URB937 is potent at attenuating pain-related behaviors in animal models, suggesting that it might offer a radically innovative approach to pain therapy. Our proposal has three primary goals aimed at testing this hypothesis: (1) Further characterize the analgesic properties of URB937. We will profile the effects of oral URB937 in industry-appropriate preclinical models of post-operative pain and visceral pain/referred hyperalgesia. (2) Compare the analgesic efficacy of URB937 with that of other analgesics. We will compare the efficacy of URB937 with that of clinically used analgesics, including opiates (morphine), non- steroidal anti-inflammatory drugs (indomethacin) and gabapentin. (3) Determine whether URB937 produces sideeffects similar to those caused by other analgesics. Clinically used analgesics cause a series of common side effects that include gastric irritation, constipation and sedation. Previous work in our lab has shown that URB937 produces no gastric irritationafter oral dosing. We will test now whether URB937 causes constipation or sedation, using morphine and gabapentin as comparators. If the results of these studies show that URB937 is equal or superior to its comparators, we will apply for STTR Phase 2 funding to move forward the preclinical development of URB937. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Current analgesic drugs are effective in only 25% of patients and can cause a variety of adverse events by acting on brain cells. We recently discovered a new class of medications, called 'peripheral FAAH inhibitors', which alleviate pain in experimental animals without entering the brain. Here, we propose to lay the groundwork needed to translate this research finding into a safe and effective treatment for human pain conditions.