• Bi-Yu Yuan, Wei-Zhe Liu, Xiao-Fang Wang, Yu-Zhe Zhang, Dai-Jun Yang, and Chang-Lin Wang.
• School of Life Science and Technology, Harbin Institute of Technology, 92 West Dazhi Street, Harbin 150001, China.
• Peptides. 2018 Aug 1; 106: 96-101.

AbstractFor clinical use, it is essential to develop potent endomorphin (EM) analogs with reduced antinociceptive tolerance. In the present study, the antinociceptive activities and tolerance development of four potent EM-1 analogs with C-terminal oligoarginine-conjugation was evaluated and compared in the radiant heat paw withdrawal test. Following intracerebroventricular (i.c.v.) administration, all analogs 1-4 produced potent and prolonged antinociceptive effects. Notably, analogs 2 and 4 with the introduction of D-Ala in position 2 exhibited relatively higher analgesic potencies than those of analogs 1 and 3 with β-Pro substitution, consistent with their μ-opioid binding characteristic. In addition, at a dose of 50 μmol/kg, endomorphin-1 (EM-1) failed to produce any significant antinociceptive activity after peripheral administration, whereas analogs 1-4 induced potent antinociceptive effects with an increased duration of action. Herein, our results indicated the development of antinociceptive tolerance to EM-1 and morphine at the supraspinal level on day 7. By contrast, analogs 1-4 decreased the antinociceptive tolerance. Furthermore, subcutaneous (s.c.) administration of morphine at 50 μmol/kg also developed the antinociceptive tolerance, whereas the extent of tolerance developed to analogs 1-4 was largely reduced. Especially, analog 4 exhibited non-tolerance-forming antinociception after peripheral administration. The present investigation gave the evidence that C-terminal conjugation of EM-1 with oligoarginine vector will facilitate the development of novel opioid analgesics with reduced opioid tolerance.Copyright © 2018 Elsevier Inc. All rights reserved.

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