Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord.

Journal Article (Journal Article)

An increasing body of evidence suggests that endothelin-converting enzyme-2 (ECE-2) is a non-classical neuropeptide processing enzyme. Similar to other neuropeptide processing enzymes, ECE-2 exhibits restricted neuroendocrine distribution, intracellular localization, and an acidic pH optimum. However, unlike classical neuropeptide processing enzymes, ECE-2 exhibits a non-classical cleavage site preference for aliphatic and aromatic residues. We previously reported that ECE-2 cleaves a number of neuropeptides at non-classical sites in vitro; however its role in peptide processing in vivo is poorly understood. Given the recognized roles of neuropeptides in pain and opiate responses, we hypothesized that ECE-2 knockout (KO) mice might show altered pain and morphine responses compared with wild-type mice. We find that ECE-2 KO mice show decreased response to a single injection of morphine in hot-plate and tail-flick tests. ECE-2 KO mice also show more rapid development of tolerance with prolonged morphine treatment and fewer signs of naloxone-precipitated withdrawal. Peptidomic analyses revealed changes in the levels of a number of spinal cord peptides in ECE-2 KO as compared to wild-type mice. Taken together, our findings suggest a role for ECE-2 in the non-classical processing of spinal cord peptides and morphine responses; however, the precise mechanisms through which ECE-2 influences morphine tolerance and withdrawal remain unclear.

Full Text

Duke Authors

Cited Authors

  • Miller, LK; Hou, X; Rodriguiz, RM; Gagnidze, K; Sweedler, JV; Wetsel, WC; Devi, LA

Published Date

  • December 2011

Published In

Volume / Issue

  • 119 / 5

Start / End Page

  • 1074 - 1085

PubMed ID

  • 21972895

Pubmed Central ID

  • PMC3217172

Electronic International Standard Serial Number (EISSN)

  • 1471-4159

Digital Object Identifier (DOI)

  • 10.1111/j.1471-4159.2011.07513.x


  • eng

Conference Location

  • England