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