title: Mice deficient in endothelin-converting enzyme-2 exhibit abnormal responses to morphine and altered peptide levels in the spinal cord.
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.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York, USA.
authors.forename: Lydia K
authors.initials: LK
authors.lastname: Miller
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Hou
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gagnidze
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Sweedler
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D013116:Spinal Cord / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology
chemical_list: D009479:Neuropeptides; D009020:Morphine; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606926:Ece2 protein, mouse; D000072396:Endothelin-Converting Enzymes