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.