Peripheral FAAH inhibitor, URB937, as an opioid-sparing analgesic for chronic pain.

PROJECT SUMMARY
Opioid drugs are powerful analgesicsbut their side effect profile strongly limits their useIndeedtheir
addictive properties have led to an epidemic of abuse in the US that accounts forof the global
utilization of prescription opioid analgesics in the USwith a market of over $billion per yearPrevious
studies have shown that the endocannabinoid neurotransmitteranandamidecontrols nociception in
mammals through a predominantly peripheral mechanismThe biological actions of anandamide are
terminated by the enzyme fatty acid amide hydrolaseFAAHWe have recently discovered a novel class of
small molecule inhibitors that block FAAH activity exclusively outside the central nervous systemCNSThe prototype member of this classURBexerts profound and long lasting analgesic effects in a variety
of animal modelssuggesting that peripheral FAAH inhibition may offer a transformative approach to pain
therapy by providing a means to reduce the need for opioid analgesicsPrevious selectivitysafety and
pharmacokinetics studies have identified URBas a lead candidate for preclinical developmentThe
present proposal will assess the pharmacodynamics interactions between URBand opioids in two sets
of mouse and rat modelsChronic pain modelsWe will compare the analgesic effects of different
dosages of URBand two commonly abused opioid analgesicshydrocodone and oxycodonein two
preclinical models of chronic neuropathic and inflammatory painSub effective and median effectiveEDdoses of each compound will be selected and combined to investigate potential synergistic effectsPotential
sex specific differences will also be exploredModels of opiate addiction and constipationWe will
examine the effects of URBon three unwanted effects caused by the administration of opioid
analgesicswhich could be affected by the combination of both drugsself administrationwithdrawaland
constipationIf the proposed activities show thatithe analgesic actions of URBare synergistic with
those of oxycodone and hydrocodoneandiiURBdoes not aggravate the side effects of these opioid
drugswe will seek further funding in the private or public financial market for the preclinical development of
URBas an opioid sparing analgesic for chronic pain PROJECT NARRATIVE
Prescription opioids are potent painkillersbut their use can cause addiction and other serious side effectsHerewe propose a series of preclinical experiments to determine whether the compound URBa drug
that boosts the actions of natural cannabis like substances outside the brainmight be used to replace or
complement opioids in the clinic