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The spinal anti-allodynic effects of endomorphin analogs with C-terminal hydrazide modification in neuropathic pain model.

Authors
  • Zhang, Yu-Zhe1
  • Yang, Wen-Jiao1
  • Wang, Xiao-Fang2
  • Wang, Meng-Meng1
  • Zhang, Yao1
  • Gu, Ning3
  • Wang, Chang-Lin4
  • 1 School of Life Science and Technology, Harbin Institute of Technology, 92 West Dazhi Street, Harbin, 150001, China. , (China)
  • 2 Jiangxi University of Traditional Chinese Medicine, Nanchang, China. , (China)
  • 3 School of Life Science and Technology, Harbin Institute of Technology, 92 West Dazhi Street, Harbin, 150001, China. Electronic address: [email protected] , (China)
  • 4 School of Life Science and Technology, Harbin Institute of Technology, 92 West Dazhi Street, Harbin, 150001, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Peptides
Publication Date
Dec 01, 2020
Volume
134
Pages
170407–170407
Identifiers
DOI: 10.1016/j.peptides.2020.170407
PMID: 32926948
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The present study was undertaken to further investigate the spinal anti-allodynic effects of endomorphins (EMs) and their C-terminal hydrazide modified analogs EM-1-NHNH2 and EM-2-NHNH2 in the spared nerve injury (SNI) model of neuropathic pain in mice. Our results demonstrated that intrathecal (i.t.) administration of endomorphin-1 (EM-1), endomorphin-2 (EM-2), EM-1-NHNH2 and EM-2-NHNH2 produced potent anti-allodynic effects ipsilaterally in neuropathic pain model. Judging from the area under the curve (AUC) values, these two analogs exhibited higher antinociception than their parent peptides. Moreover, they also displayed significant antinociceptive effects in the contralateral paw administered intrathecally. Interestingly, EM-1 and its analog EM-1-NHNH2 displayed their antinociception probably by μ2-opioid receptor subtype since the μ1-opioid receptor antagonist naloxonazine didn't significantly block the anti-allodynia of EM-1 and EM-1-NHNH2, which implied a same opioid mechanism. However, the anti-allodynia induced by EM-2, but not EM-2-NHNH2 was significantly reduced by both μ1-opioid antagonist, naloxonazine and κ-antagonist, nor-binaltorphamine (nor-BNI), indicating multiple opioid receptors were involved in the anti-allodynic effects of EM-2. Most importantly, EM-1-NHNH2 decreased the antinociceptive tolerance, and EM-2-NHNH2 displayed non-tolerance-forming antinociception. Therefore, C-terminal amide to hydrazide conversion changed the spinal antinociceptive profiles of EMs in neuropathic pain. The present investigation is of great value in the development of novel opioid therapeutics against neuropathic pain. Copyright © 2020 Elsevier Inc. All rights reserved.

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