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.
Department of Clinical Medicine, Gansu Health Vocational College, 60 Donggang West Road, Lanzhou, 730000, PR China.
Neuropharmacology. 2020 Sep 15;175:108178. doi: 10.1016/j.neuropharm.2020.108178. Epub 2020 Jun 13.
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 NPFF or NPFF 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 and NPFF 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-NH induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH 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.
药理学证据表明，神经肽 FF（NPFF）和大麻素系统之间存在功能相互作用，而大麻素与 NPFF 受体激动剂神经肽 VF（NPVF）联合使用可产生无耐受的镇痛作用。在本研究中，合成了一种包含内源性大麻素肽 VD-hemopressin(α)（VD-Hpα）和 NPVF 药效基团的嵌合肽 VF-13，并对其进行了药理学评价。体外实验结果表明，VF-13 可显著上调稳定表达 CB1 受体的 CHO 细胞中细胞外信号调节激酶 1/2（ERK1/2）的磷酸化水平，并抑制稳定表达 NPFF 或 NPFF 受体的 HEK293 细胞中forskolin 诱导的 cAMP 积累。此外，VF-13 可通过 CB1 和 NPFF 受体诱导 Neuro 2A 细胞的轴突生长。这些结果表明，VF-13 在体外对 CB1、NPFF 和 NPFF 受体具有多功能激动作用。有趣的是，脑室注射 VF-13 通过 TRPV1 受体在小鼠尾夹和角叉菜胶诱导的炎症性疼痛模型中产生剂量依赖性镇痛作用。相比之下，参考化合物（m）VD-Hpα-NH 通过 CB1 受体介导产生了脊髓上镇痛作用。此外，皮下注射（m）VD-Hpα-NH 和 VF-13 在角叉菜胶诱导的炎症性疼痛模型中产生了显著的镇痛作用。在四联体测定中，我们的数据表明，VF-13 脑室注射后会引起体温降低，但不会引起僵住和活动减少。值得注意的是，VF-13 在急性和炎症性疼痛模型中连续治疗 6 天，可产生无耐受形成的镇痛作用。此外，VF-13 对胃肠道转运、戊巴比妥钠诱导的镇静、食物摄入和在脊髓水平的运动协调没有明显影响。综上所述，新型嵌合肽 VF-13 由 VD-Hpα 和 NPVF 组成，在临床前疼痛模型中产生无耐受形成的镇痛作用，且减少了与大麻素相关的副作用。
