RB101-mediated Protection of Endogenous Opioids: Potential Therapeutic Utility?

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.