Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance
Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance
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EN-9 的药理学特征，EN-9 是内吗啡肽 2 和神经肽 FF 的新型嵌合肽，可产生有效的镇痛活性和有限的耐受性
DOI：
10.1016/j.neuropharm.2016.03.017
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发表时间：
2016-09
影响因子：
4.7
通讯作者：
Wang, Rui
中科院分区：
文献类型：
--
作者：
Xu, Biao;Zhang, Meng-na;Fang, Quan;Wang, Rui
越来越多的证据表明神经肽 FF (NPFF) 和阿片类药物（包括内源性阿片类药物）之间存在功能性相互作用。在目前的工作中，合成了 EN-9，一种含有内源性阿片类药物内吗啡肽 2 (EM-2) 和 NPFF 功能域的嵌合肽，并进行了药理学表征。体外 cAMP 测定表明 EN-9 是 κ-阿片类药物、NPFF1 和 NPFF2 受体的多功能激动剂。在小鼠甩尾测试中，脑室内 (i.c.v.) 施用 EN-9 产生显着的镇痛作用，ED50 值为 13.44 nmol，其持续时间比 EM-2 更长。此外，EN-9 在静脉内 (i.v.) 和皮下 (s.c.) 注射后均诱导有效的镇痛作用。此外，使用阿片类药物和 NPFF 受体拮抗剂的实验表明，EN-9 的中枢镇痛作用主要由 κ-阿片类受体介导，与 NPFF 受体无关。值得注意的是，EN-9 的中枢抗伤害作用在 6 天的重复静脉注射期间并未降低。注射。重复静脉注射EN-9 与 NPFF1 和 NPFF2 受体拮抗剂 RF9 一起给药导致镇痛效力逐渐丧失，与耐受性的发展一致。此外，EN-9 的中枢给药仅在 60 nmol 高剂量时才会诱导位置条件厌恶，而在低剂量时则不会。在脊髓上水平，只有高剂量的 EN-9（60 nmol，静脉注射）才能通过 NPFF 受体抑制胃肠道转运。同样，高剂量（10 和 30 mg/kg，静脉注射）EN-9 的全身给药也会抑制胃肠道转运。总而言之，κ-阿片类药物和 NPFF 受体 EN-9 的多功能激动剂产生了有效的、非耐受性的镇痛作用，且副作用有限。
Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1and NPFF2receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1and NPFF2receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.
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DOI：
--
发表时间：
1984-08
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
F. Porreca;H. Mosberg;R. Hurst;V. J. Hruby;Thomas F. Burks
通讯作者：
F. Porreca;H. Mosberg;R. Hurst;V. J. Hruby;Thomas F. Burks
影响因子：
--
作者：
F. Gusovsky
通讯作者：
F. Gusovsky
DOI：
--
发表时间：
1993
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
R. Bals-Kubik;A. Ableitner;A. Herz;T. Shippenberg
通讯作者：
R. Bals-Kubik;A. Ableitner;A. Herz;T. Shippenberg
影响因子：
3.2
作者：
Yuan Y;Arnatt CK;Li G;Haney KM;Ding D;Jacob JC;Selley DE;Zhang Y
通讯作者：
Zhang Y
DOI：
--
发表时间：
1983
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
P. Vonvoigtlander;R. Lahti;J. H. Ludens
通讯作者：
P. Vonvoigtlander;R. Lahti;J. H. Ludens