BN-9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance-forming antinociception in mice
BN-9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance-forming antinociception in mice
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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
DOI：
10.1111/bph.13489
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发表时间：
2016-06-01
影响因子：
7.3
通讯作者：
Wang, Rui
中科院分区：
文献类型：
--
作者：
Li, Ning;Han, Zheng-lan;Wang, Rui
神经肽FF（NPFF）是一种内源性阿片调节肽。本研究合成了含有阿片和NPFF药效团的嵌合肽BN-9，并对其进行了体外结构表征，用体外cAMP测定法研究了BN-9对阿片和NPFF受体的促接近活性。在小鼠甩尾和福尔马林试验中评价BN-9的抗伤害感受活性。此外，在旋转棒、抗伤害耐受、奖赏和胃肠道传输试验中研究了其副作用。在cAMP测定中，KEY STBN-9作为一种新的多功能激动剂在μ、δ、κ、NPFF 1和NPFF 2受体上起作用。在甩尾试验中，BN-9产生剂量相关的抗伤害性感受，并且与吗啡大致等效;这种抗伤害性感受被mu和kappa受体拮抗剂阻断，但不被d受体拮抗剂阻断。在福尔马林试验中，脊髓上给予BN-9产生显著的镇痛作用。值得注意的是，重复施用BN-9在8天内产生镇痛而不损失效力。相反，BN-9与NPFF受体拮抗剂RF 9的重复i. c. v.共给药产生显著的抗伤害耐受性。此外，i. c. v. BN-9诱导条件性位置偏爱。当给予相同的路线，BN-9有一个超过8倍的ED 50值为胃肠道传输抑制相比，ED 50值为antinociception.CONCLUSIONS和IMPLICATIONSBN-9产生了强大的，非耐受性形成镇痛与胃肠道传输的有限抑制。由于BN-9能够激活阿片样物质和NPFF系统，这为开发具有最小副作用的新型镇痛剂提供了一种有趣的方法。
BACKGROUND AND PURPOSENeuropeptide FF (NPFF) behaves as an endogenous opioid-modulating peptide. In the present study, the opioid and NPFF pharmacophore-containing chimeric peptide BN-9 was synthesized and pharmacologically characterized.EXPERIMENTAL APPROACHAgonist activities of BN-9 at opioid and NPFF receptors were characterized in in vitro cAMP assays. Antinociceptive activities of BN-9 were evaluated in the mouse tail-flick and formalin tests. Furthermore, its side effects were investigated in rotarod, antinociceptive tolerance, reward and gastrointestinal transit tests.KEY RESULTSBN-9 acted as a novel multifunctional agonist at mu, delta, kappa, NPFF1 and NPFF2 receptors in cAMP assays. In the tail-flick test, BN-9 produced dose-related antinociception and was approximately equipotent to morphine; this antinociception was blocked by mu and kappa receptor antagonists, but not by the d receptor antagonist. In the formalin test, supraspinal administration of BN-9 produced significant analgesia. Notably, repeated administration of BN-9 produced analgesia without loss of potency over 8 days. In contrast, repeated i.c.v. co-administration of BN-9 with the NPFF receptor antagonist RF9 produced significant antinociceptive tolerance. Furthermore, i.c.v. BN-9 induced conditioned place preference. When given by the same routes, BN-9 had a more than eightfold higher ED50 value for gastrointestinal transit inhibition compared with the ED50 values for antinociception.CONCLUSIONS AND IMPLICATIONSBN-9 produced a robust, nontolerance-forming analgesia with limited inhibition of gastrointestinal transit. As BN-9 is able to activate both opioid and NPFF systems, this provides an interesting approach for the development of novel analgesics with minimal side effects.