heroin and anandamide

Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)

Topics: Acetamides; Analgesics; Analgesics, Opioid; Animals; Arachidonic Acid; Arachidonic Acids; Carbamates; Carrageenan; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Endocannabinoids; Glycerides; Heroin; Hydrolysis; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Neuralgia; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Sciatic Nerve; Self Administration

Topics: Amides; Animals; Arachidonic Acids; Brain; Cannabinoids; Dronabinol; Endocannabinoids; Enkephalin, Leucine; Fatty Acids, Unsaturated; Heroin; Humans; Morphine; Polyunsaturated Alkamides; Receptors, Opioid; Structure-Activity Relationship; Tea