title: Structure-constrained endomorphin analogs display differential antinociceptive mechanisms in mice after spinal administration.
abstract: We previously reported a series of novel endomorphin analogs with unnatural amino acid modifications. These analogs display good binding affinity and functional activity toward the μ opioid receptor (MOP). In the present study, we further investigated the spinal antinociceptive activity of these compounds. The analogs were potent in several nociceptive models. Opioid antagonists and antibodies against several endogenous opioid peptides were used to determine the mechanisms of action of these peptides. Intrathecal pretreatment with naloxone and β-funaltrexamine (β-FNA) effectively inhibited analog-induced analgesia, demonstrating that activity of the analogs is regulated primarily through MOP. Antinociception induced by analog 2 through 4 was not reversed by δ opioid receptor (DOP) or κ opioid receptor (KOP) antagonist; antibodies against dynorphin-A (1-17), dynorphin-B (1-13), and Leu5/Met5-enkephalin had no impact on the antinociceptive effects of these analogs. In contrast, antinociceptive effects induced by a spinal injection of the fluorine substituted analog 1 were significantly reversed by KOP antagonism. Furthermore, intrathecal pretreatment with antibodies against dynorphin-B (1-13) attenuated the antinociceptive effect of analog 1. These results indicate that the antinociceptive activity exerted by intrathecally-administered analog 1 is mediated, in part, through KOP with increased release of dynorphin-B (1-13). The chemical modifications used in the present study may serve as a useful tool to gain insight into the mechanisms of endomorphins activity.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Zhaojuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Kezhou
authors.initials: K
authors.lastname: Wang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China.
authors.forename: Linqing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Department of Pharmacology, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, PR China. Electronic address: wangrui@lzu.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000276:immunology; D004399:Dynorphins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D018847:Opioid Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010147:Pain Measurement; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D017480:Receptors, sigma / Q000037:antagonists & inhibitors
chemical_list: D000701:Analgesics, Opioid; D000906:Antibodies; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; C105293:endomorphin 1; D005461:Fluorine; D009270:Naloxone; C105294:endomorphin 2; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D009271:Naltrexone; C024524:beta-funaltrexamine; D004399:Dynorphins
keywords: Antagonist; Antibody; Dynorphin; Endomorphin; Spinal antinociception