PMID- 32544481 OWN - NLM STAT- MEDLINE DCOM- 20210923 LR - 20210923 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 175 DP - 2020 Sep 15 TI - VF-13, a chimeric peptide of VD-hemopressin(alpha) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects. PG - 108178 LID - S0028-3908(20)30246-X [pii] LID - 10.1016/j.neuropharm.2020.108178 [doi] AB - Pharmacological evidence indicated a functional interaction between neuropeptide FF (NPFF) and cannabinoid systems, and the cannabinoids combined with the NPFF receptor agonist neuropeptide VF (NPVF) produced antinociception without tolerance. In the present study, VF-13, a chimeric peptide containing the pharmacophores of the endogenous cannabinoid peptide VD-hemopressin(alpha) (VD-Hpalpha) and NPVF, was synthesized and pharmacologically evaluated. In vitro, VF-13 significantly upregulated the phosphorylated level of extracellular signal-regulated kinase 1/2 (ERK1/2) in CHO cells stably expressing CB1 receptors and inhibited forskolin-induced cAMP accumulation in HEK293 cells stably expressing NPFF(1) or NPFF(2) receptors. Moreover, VF-13 induced neurite outgrowth in Neuro 2A cells via CB1 and NPFF receptors. These results suggest that VF-13 exhibits multifunctional agonism at CB1, NPFF(1) and NPFF(2) receptors in vitro. Interestingly, intracerebroventricular VF-13 produced dose-dependent antinociception in mouse models of tail-flick and carrageenan-induced inflammatory pain via the TRPV1 receptor. In contrast, the reference compound (m)VD-Hpalpha-NH(2) induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpalpha-NH(2) and VF-13 produced significant antinociception in carrageenan-induced inflammatory pain model. In the tetrad assay, our data demonstrated that VF-13 elicited hypothermia, but not catalepsy and hypoactivity after intracerebroventricular injection. Notably, VF-13 produced non-tolerance forming antinociception over 6 days treatment in both acute and inflammatory pain models. Furthermore, VF-13 had no apparent effects on gastrointestinal transit, pentobarbitone-induced sedation, food intake, and motor coordination at the supraspinal level. In summary, VF-13, a novel chimeric peptide of VD-Hpalpha and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved. FAU - Xu, Biao AU - Xu B AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Xiao, Jian AU - Xiao J AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Xu, Kangtai AU - Xu K AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Qinqin AU - Zhang Q AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Chen, Dan AU - Chen D AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Run AU - Zhang R AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Mengna AU - Zhang M AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhu, Hanwen AU - Zhu H AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Niu, Jiandong AU - Niu J AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zheng, Ting AU - Zheng T AD - Department of Clinical Medicine, Gansu Health Vocational College, 60 Donggang West Road, Lanzhou, 730000, PR China. FAU - Li, Ning AU - Li N AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Xiaoyu AU - Zhang X AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Fang, Quan AU - Fang Q AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. Electronic address: fangq@lzu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200613 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Analgesics) RN - 0 (Neuropeptides) RN - 0 (Oligopeptides) RN - 0 (Peptides) RN - 0 (Receptor, Cannabinoid, CB1) RN - 0 (VDPVNFKLLSH-OH) RN - 0 (neuropeptide VF) SB - IM MH - Analgesics/administration & dosage/metabolism MH - Animals MH - HEK293 Cells MH - Humans MH - Male MH - Mice MH - Neuropeptides/*metabolism MH - Nociception/*physiology MH - Oligopeptides/administration & dosage/*metabolism MH - Pain Measurement/drug effects MH - Peptides/administration & dosage/metabolism MH - Receptor, Cannabinoid, CB1/*metabolism MH - *Signal Transduction OTO - NOTNLM OT - Analgesia OT - Cannabinoid OT - Chimeric peptide OT - Neuropeptide FF OT - Non-tolerance EDAT- 2020/06/17 06:00 MHDA- 2021/09/24 06:00 CRDT- 2020/06/17 06:00 PHST- 2020/01/15 00:00 [received] PHST- 2020/05/05 00:00 [revised] PHST- 2020/05/31 00:00 [accepted] PHST- 2020/06/17 06:00 [pubmed] PHST- 2021/09/24 06:00 [medline] PHST- 2020/06/17 06:00 [entrez] AID - S0028-3908(20)30246-X [pii] AID - 10.1016/j.neuropharm.2020.108178 [doi] PST - ppublish SO - Neuropharmacology. 2020 Sep 15;175:108178. doi: 10.1016/j.neuropharm.2020.108178. Epub 2020 Jun 13.