VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects
VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects
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VF-13 是 VD-加压素 (α) 和神经肽 VF 的嵌合肽，可产生有效的镇痛作用，并减少大麻素相关的副作用
DOI：
10.1016/j.neuropharm.2020.108178
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发表时间：
2020-06
影响因子：
4.7
通讯作者：
Fang Q
中科院分区：
文献类型：
--
作者：
Xu B;Xiao J;Xu KT;Zhang QQ;Chen D;Zhang R;Zhang MN;Zhu HW;Niu JD;Zheng T;Li N;Zhang XY;Fang Q
药理学证据表明神经肽FF（NPFF）与大麻素系统之间存在功能性相互作用，大麻素与NPFF受体激动剂神经肽VF（NPVF）结合可产生无耐受性的抗伤害感受作用。本研究合成了一种含有内源性大麻素肽VD-加压素（α）（VD-Hpα）和NPVF药效团的嵌合肽VF-13，并对其进行了体外评价。在体外，VF-13显著上调稳定表达CB 1受体的CHO细胞中细胞外信号调节激酶1/2（ERK 1/2）的磷酸化水平，并抑制稳定表达NPFF 1或NPFF 2受体的HEK 293细胞中毛喉素诱导的cAMP积累。此外，VF-13通过CB 1和NPFF受体诱导Neuro 2A细胞中的神经突生长。这些结果表明VF-13在体外对CB 1、NPFF 1和NPFF 2受体具有多功能激动作用。有趣的是，脑室VF-13通过TRPV 1受体在甩尾和角叉菜胶诱导的炎性疼痛小鼠模型中产生剂量依赖性抗伤害感受。相反，参比化合物（m）VD-Hpα-NH 2诱导CB 1受体介导的脊髓上抗伤害感受。此外，皮下注射VD-Hpα-NH 2和VF-13对角叉菜胶诱导的炎性疼痛模型产生显著的镇痛作用。在四分体试验中，我们的数据表明，VF-13引起低体温，但不僵硬和活动减退后，脑室内注射。值得注意的是，VF-13在急性和炎性疼痛模型中在6天治疗中产生非耐受性形成抗伤害感受。此外，VF-13对胃肠转运、戊巴比妥诱导的镇静、食物摄入和脊髓上水平的运动协调没有明显影响。总之，VF-13是一种新型的VD-Hpα和NPVF嵌合肽，在临床前疼痛模型中产生非耐受性形成抗伤害感受，降低了大麻素相关的副作用。
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 NPFF1or NPFF2receptors. 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, NPFF1and NPFF2receptors 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-NH2induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH2and 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.
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影响因子：
3.7
作者：
Burston JJ;Sagar DR;Shao P;Bai M;King E;Brailsford L;Turner JM;Hathway GJ;Bennett AJ;Walsh DA;Kendall DA;Lichtman A;Chapman V
通讯作者：
Chapman V
DOI：
10.1073/pnas.130181897
发表时间：
2000-06-20
影响因子：
11.1
作者：
Foran, SE;Carr, DB;Kream, RM
通讯作者：
Kream, RM
BN-9 是一种具有混合阿片类药物和神经肽 FF 受体激动特性的嵌合肽，可在小鼠体内产生非耐受性抗伤害作用
影响因子：
7.3
作者：
Li, Ning;Han, Zheng-lan;Wang, Rui
通讯作者：
Wang, Rui
影响因子：
7.6
作者：
Navarrete, Francisco;Rodriguez-Arias, Marta;Manzanares, Jorge
通讯作者：
Manzanares, Jorge
DOI：
10.1016/j.pnpbp.2017.07.012
发表时间：
2017-10
影响因子：
5.6
作者：
N. Silva;F. Gomes;Miriam D. Fonseca;R. Mechoulam;A. Breuer;T. Cunha;F. Guimarães
通讯作者：
N. Silva;F. Gomes;Miriam D. Fonseca;R. Mechoulam;A. Breuer;T. Cunha;F. Guimarães