Enkephalinase

Enkephalinase refers to a class of proteolytic enzymes that inactivate enkephalins, endogenous opioid peptides derived from proenkephalin. By cleaving enkephalins, enkephalinases regulate the duration and intensity of opioid signaling in the nervous system and peripheral tissues, contributing to the modulation of pain, mood, and autonomic function.

Among enkephalinases, neprilysin (neutral endopeptidase, NEP) is the best characterized. It is a zinc-dependent membrane-bound metallopeptidase that hydrolyzes enkephalins at internal peptide bonds and has a broad substrate range, including other neuropeptides such as substance P, bradykinin, and natriuretic peptides. NEP activity shapes enkephalinergic signaling in multiple brain regions and in peripheral tissues.

Physiological and pathophysiological roles: In the central nervous system, enkephalinase limits analgesic signaling; inhibition of enkephalinase can enhance endogenous analgesia in animal models. In the periphery it can influence cardiovascular and renal function via peptide metabolism, reflecting its widespread role in peptide regulation beyond pain.

Therapeutic relevance: Specific enkephalinase inhibitors, such as thiorphan, are used in research to augment enkephalin signaling. Clinically, neprilysin inhibitors (for example, sacubitril in combination therapy for heart failure) increase levels of natriuretic peptides and other substrates, illustrating how enkephalinase inhibition can affect endogenous peptide signaling beyond pain mechanisms.