The effects of the synthetic nocistatin on blood vessel activities

Nocistatin was synthesized by the solid-phase peptide synthesis method. Its effects on rat systemic arterial pressure; rat hindquarter vascular bed resistance; tension of rabbit pectoral, abdominal, femoral aorta muscle strips without endothelium; and nociceptin induced decreases of rat systemic arterial pressure were determined. The results showed that nocistatin can increase the systemic arterial pressure, increase the hindquarter vascular bed resistance and induce the contraction significantly of abdominal, femoral aorta muscle strips without endotheiium; it has no significant effect on tension of pectoral aorta muscle strips, it cannot antagonize significantly the decrease of rat systemic arterial pressure induced by nociceptin. These results suggest that nocistatin has some important effects on blood vessel activities.     

Cebranopadol as a Novel Promising Agent for the Treatment of Pain

Opioids are used to treat pain, but despite their effectiveness, they possess several side effects such as respiratory depression, tolerance and physical dependence. Cebranopadol has been evaluated as a solution to this problem. The compound acts on the mu opioid receptor and the nociceptin/orphanin receptor and these receptors co-activation can reduce opioid side-effects without compromising analgesia. In the present review, we have compiled information on the effects of cebranopadol, its pharmacokinetics, and clinical trials involving cebranopadol, to further explore its promise in pain management.     

多肽生化和手性药物的研究

综述了我研究室近年来在多肽生化和手性药物领域中的研究进展：①进行了抗癌药物 Ａ Ｍ Ｄ 类似物的全新设计、化学全合成、与 Ｄ Ｎ Ａ 结合活性和构效关系研究； ②研究了新皮啡肽类似物及其自旋标记衍生物和孤儿受体的天然配基孤啡肽的构效关系；③进行了 Ｄ Ｎ Ａ 结合蛋白结构域：锌指及其突变体的合成及与寡聚核苷酸结合能力的研究； ④将稳定的氮氧自由基标记肽类药物血管紧张素Ⅱ，建立了一种使生物活性肽带上自旋标记的简便方法， 用以研究肽类药物与受体间的相互作用及自由基对肽类药物生理活性的影响；⑤为解决许多手性药物合成中的难题，开发了一个构筑手性季碳的新方法； ⑥研究了手性催化剂作用下二乙基锌对醛的不对称加成反应，为手性药物的研制提供了新反应     

Effect of nocistatin in pain modulation

Using tail-flick latency as the nociceptive index and von Frey hair to measure the mechanical allodynia, the aim of the present study is to determine whether nocistatin, injected intracerebroventricularly (i.c.v.), would reverse the anti-morphine effect of orphanin FQ (OFQ), and, injected i.c.v. or intrathecally (Lt.), would inhibit the mechanical allodynia in a L5 and L6 spinal nerve ligation model of neuropathic pain in rats. The results show that i.c.v. injection of nocistatin produces no significant changes in the TFL, nor does it affect morphine analgesia. In addition, i.c.v. or i.t. nocistatin produces no significant changes in withdrawal threshold of the nerve-lesioned hind paw. However, nocistatin significantly reverses the antagonistic effect of OFQ on morphine analgesia when it was coinjected i.c.v. with OFQ. The results suggest that nocistatin can reverse the anti-morphine effect of OFQ in rat brain, but cannot inhibit the mechanical allodynia of neuropathic pain in rat brain and spinal cord.     

Synthesis, structure-activity relationship of nociceptin and its fragments

Nociceptin (NC) and its 4 fragments have been synthesized by solid phase peptide synthesis. Their hypertensive activity and mechanism, MVD assay and structure-activity relationship have been investigated. Results show that NC(1-13)NH2 is the smallest fragment that shares the same activity with NC. The truncation of C-terminal not only leads the decrease of receptor affinity but also the changes of receptor selectivity. The entire sequence may not be required for the full activity since NC(1-13)NH2 is as active as NC. Arg-Lys at the 12-13 position of C-terminal plays an important role in the activity of NC. The hypotensive activity of NC does not antagonize the hypertensive activity of renin-angiotensin system.     

Spotlight on Nociceptin/Orphanin FQ Receptor in the Treatment of Pain

In our society today, pain has become a main source of strain on most individuals. It is crucial to develop novel treatments against pain while focusing on decreasing their adverse effects. Throughout the extent of development for new pain therapies, the nociceptin/orphanin FQ receptor (NOP receptor) has appeared to be an encouraging focal point. Concentrating on NOP receptor to treat chronic pain with limited range of unwanted effects serves as a suitable alternative to prototypical opioid morphine that could potentially lead to life-threatening effects caused by respiratory depression in overdose, as well as generate abuse and addiction. In addition to these harmful effects, the uprising opioid epidemic is responsible for becoming one of the most disastrous public health issues in the US. In this article, the contributing molecular and cellular structure in controlling the cellular trafficking of NOP receptor and studies that support the role of NOP receptor and its ligands in pain management are reviewed.     

Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH₂) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund’s adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.     

多能硫杆菌1,5-二磷酸核酮糖羧化酶/加氧酶基因的启动子克隆和表达

将３．４ｋｂ的多能硫杆菌１，５－二磷酸核酮糖羧化酶／加氧酶基因（ｒｂｃＬ－ｒｂｃＳ）片段亚克隆到启动子探测质粒载体ｐＫＬ６的ＨｉｎｄⅢ位点，该基因片段能够启动ｐＫＬ６的ｌａｃ基因的表达，说明３．４ｋｂ的ｒｂｃＬ－ｒｂｃＳ基因带有自己的启动子．