Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders.

The endogenous opioid system (EOS) is considered being a crucial element involved in the pathophysiology of irritable bowel syndrome (IBS) as it regulates gastrointestinal (GI) homeostasis through modulation of motility and water and ion secretion/absorption. Along with opioid receptors (ORs), the following components of EOS can be distinguished: 1. endogenous opioid peptides (EOPs), namely enkephalins, endorphins, endomorphins and dynorphins, and 2. peptidases, which regulate the metabolism (synthesis and degradation) of EOPs. Enkephalins, which are δ-opioid receptors agonists, induce significant effects in the GI tract as they act as potent pro-absorptive neurotransmitters. The action of enkephalins and other EOPs is limited, since EOPs are easily and rapidly inactivated by a natural metalloendopeptidase (enkephalinase/neprilysin) and aminopeptidase N. Studies show that the activity of EOPs can be enhanced by inhibition of these enzymes. In this review, we discuss the antidiarrheal and antinociceptive potential of enkephalinase inhibitors. Furthermore, our review is to answer the question whether enkephalinase inhibitors may be helpful in the future treatment of diarrhea predominant functional GI disorders.