VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects.

Abstract

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(α) (VD-Hpα) 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 NPFF1 or NPFF2 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, NPFF1 and NPFF2 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-Hpα-NH2 induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH2 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-Hpα and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects.

• Authors: Biao Xu, Jian Xiao, Kangtai Xu, Qinqin Zhang, Dan Chen, Run Zhang, Mengna Zhang, Hanwen Zhu, Jiandong Niu, Ting Zheng, Ning Li, Xiaoyu Zhang, Quan Fang
• Journal: Neuropharmacology (Neuropharmacology) Vol. 175 Pg. 108178 (09 15 2020) ISSN: 1873-7064 [Electronic] England
• PMID: 32544481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Neuropeptides
• Oligopeptides
• Peptides
• Receptor, Cannabinoid, CB1
• VDPVNFKLLSH-OH
• neuropeptide VF

Topics

• Analgesics (administration & dosage, metabolism)
• Animals
• HEK293 Cells
• Humans
• Male
• Mice
• Neuropeptides (metabolism)
• Nociception (physiology)
• Oligopeptides (administration & dosage, metabolism)
• Pain Measurement (drug effects)
• Peptides (administration & dosage, metabolism)
• Receptor, Cannabinoid, CB1 (metabolism)
• Signal Transduction