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

Lydia K. Miller, Xiaowen Hou, Ramona M. Rodriguiz, Khatuna Gagnidze, Jonathan V Sweedler, William C. Wetsel, Lakshmi A. Devi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1074-1085
Number of pages12
JournalJournal of Neurochemistry
Volume119
Issue number5
DOIs
StatePublished - Dec 1 2011

Fingerprint

Endothelins
Morphine
Spinal Cord
Peptides
Enzymes
Neuropeptides
Knockout Mice
Processing
Opiate Alkaloids
Endothelin-Converting Enzymes
Pain
Naloxone
Tail
Injections

Keywords

  • differential isotopic labeling
  • morphine tolerance
  • morphine withdrawal
  • neuropeptide biosynthesis
  • opioid
  • peptidomics

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord. / Miller, Lydia K.; Hou, Xiaowen; Rodriguiz, Ramona M.; Gagnidze, Khatuna; Sweedler, Jonathan V; Wetsel, William C.; Devi, Lakshmi A.

In: Journal of Neurochemistry, Vol. 119, No. 5, 01.12.2011, p. 1074-1085.

Research output: Contribution to journalArticle

Miller, Lydia K. ; Hou, Xiaowen ; Rodriguiz, Ramona M. ; Gagnidze, Khatuna ; Sweedler, Jonathan V ; Wetsel, William C. ; Devi, Lakshmi A. / Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord. In: Journal of Neurochemistry. 2011 ; Vol. 119, No. 5. pp. 1074-1085.
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