PMID- 34351126 OWN - NLM STAT- MEDLINE DCOM- 20240208 LR - 20240208 IS - 1948-7193 (Electronic) IS - 1948-7193 (Linking) VI - 12 IP - 16 DP - 2021 Aug 18 TI - Repeated Endomorphin Analogue MEL-0614 Reduces Tolerance and Improves Chronic Postoperative Pain without Modulating the P2X7R Signaling Pathway. PG - 3124-3139 LID - 10.1021/acschemneuro.1c00418 [doi] AB - The clinical treatment of chronic postoperative pain (CPSP) remains challenging. The side effects of chronic morphine treatment limit its clinical application. MEL-0614, a novel endomorphin analogue that is highly selective and agonistic for mu opioid receptor (MOR), produces a more powerful analgesic effect than that of morphine. In this study, we explored the difference in antinociceptive tolerance and related mechanisms between MEL-0614 and morphine in CPSP induced in a skin/muscle incision and retraction (SMIR) mice model. We found that acute administration of MEL-0614 (1, 3, 5, and 10 nmol, i.t.) produced a dose-dependent analgesic effect that was superior to that of morphine in the SMIR mice model. Long-term MEL-0614 treatment (10 nmol, i.t.) did not induce tolerance compared with morphine. Notably, tolerance induced by morphine could be greatly prevented and/or inhibited via cross-administration or coadministration between MEL-0614 and morphine. In addition, MEL-0614 accelerated the recovery of postoperative pain, whereas morphine aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment. In addition, MEL-0614 did not activate microglia and the P2X7R signaling pathway and showed reduced expression iba1 and P2X7R compared with that observed after morphine administration. Release of inflammatory factors was induced by continued administration of morphine during SMIR surgery, but MEL-0614 did not promote the activation of inflammatory factors. Our results showed that MEL-0614 has superior analgesic effects in CPSP and leads to tolerance to a lesser degree than morphine. Further, MEL-0614 may be used as a promising treatment option for the long-term treatment in CPSP. FAU - Wei, Shuang AU - Wei S AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Han, Chao-Zhen-Yi AU - Han CZ AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Wang, Jing AU - Wang J AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Li, Kai AU - Li K AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Ru, Qiao-Min AU - Ru QM AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Wang, Yuan AU - Wang Y AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Ma, Meng-Tao AU - Ma MT AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Wang, Lin-Qing AU - Wang LQ AUID- ORCID: 0000-0001-5922-1332 AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Liu, Xin AU - Liu X AUID- ORCID: 0000-0002-3234-6925 AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. FAU - Wang, Rui AU - Wang R AUID- ORCID: 0000-0002-4719-9921 AD - Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210805 PL - United States TA - ACS Chem Neurosci JT - ACS chemical neuroscience JID - 101525337 RN - 0 (Analgesics, Opioid) RN - 76I7G6D29C (Morphine) RN - 0 (P2rx7 protein, mouse) RN - 0 (Receptors, Opioid, mu) RN - 0 (Receptors, Purinergic P2X7) SB - IM MH - Animals MH - Mice MH - *Analgesics, Opioid/pharmacology MH - Drug Tolerance MH - *Morphine/pharmacology MH - *Pain, Postoperative/drug therapy MH - Receptors, Opioid, mu MH - Receptors, Purinergic P2X7 MH - Signal Transduction MH - Humans MH - Disease Models, Animal OTO - NOTNLM OT - Chronic postoperative pain OT - Microglia OT - Opioid peptide OT - P2X receptor 7 OT - Tolerance EDAT- 2021/08/06 06:00 MHDA- 2021/09/04 06:00 CRDT- 2021/08/05 12:20 PHST- 2021/08/06 06:00 [pubmed] PHST- 2021/09/04 06:00 [medline] PHST- 2021/08/05 12:20 [entrez] AID - 10.1021/acschemneuro.1c00418 [doi] PST - ppublish SO - ACS Chem Neurosci. 2021 Aug 18;12(16):3124-3139. doi: 10.1021/acschemneuro.1c00418. Epub 2021 Aug 5.