title: RB101-mediated protection of endogenous opioids: potential therapeutic utility?
abstract: The endogenous opioids met- and leu-enkephalin are inactivated by peptidases preventing the activation of opioid receptors. Inhibition of enkephalin-degrading enzymes increases endogenous enkephalin levels and stimulates robust behavioral effects. RB101, an inhibitor of enkephalin-degrading enzymes, produces antinociceptive, antidepressant, and anxiolytic effects in rodents, without typical opioid-related negative side effects. Although enkephalins are not selective endogenous ligands, RB101 induces these behaviors through receptor-selective activity. The antinociceptive effects of RB101 are produced through either the mu-opioid receptor alone or through activation of both mu- and delta-opioid receptors; the antidepressant-like and anxiolytic effects of RB101 are mediated only through the delta-opioid receptor. Although little is known about the effects of RB101 on other physiologically and behaviorally relevant peptides, these findings suggest that RB101 and other inhibitors of enkephalin-degrading enzymes may have potential as novel therapeutic compounds for the treatment of pain, depression, and anxiety.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA. ejutkiew@umich.edu
authors.forename: Emily M
authors.initials: EM
authors.lastname: Jutkiewicz
mesh_terms: D000626:Aminopeptidases / Q000187:drug effects; D000818:Animals; D002766:Cholecystokinin / Q000187:drug effects / Q000378:metabolism*; D004220:Disulfides / Q000494:pharmacology*; D004743:Enkephalin, Leucine / Q000187:drug effects / Q000378:metabolism*; D004744:Enkephalin, Methionine / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011355:Prodrugs; D051381:Rats
chemical_list: D004220:Disulfides; D004791:Enzyme Inhibitors; D011355:Prodrugs; C074024:RB 101; D010649:Phenylalanine; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D002766:Cholecystokinin; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme