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.
Bioorg Med Chem. 2019 Feb 15;27(4):630-643. doi: 10.1016/j.bmc.2019.01.003. Epub 2019 Jan 4.
It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF receptor antagonist/NPFF receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF antagonism/NPFF partial agonism. Furthermore, EKR and RKE completely blocked the NPFF receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF antagonism/NPFF partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.
众所周知，阿片类镇痛药会产生副作用，包括耐受和便秘。由于神经肽 FF（NPFF）受体拮抗剂可逆转阿片类药物引起的痛觉过敏和镇痛耐受，因此本工作合成了两种分支肽，EKR 和 RKE，其中包含阿片肽内吗啡-2（EM-2）和 NPFF 受体拮抗剂 RF9。我们从体外环磷酸腺苷实验中获得的数据表明，EKR 作为一种混合的μ-、δ-阿片受体激动剂和 NPFF 受体拮抗剂/NPFF 受体部分激动剂起作用，而 RKE 作为一种多功能肽模拟物，具有μ-阿片激动作用和 NPFF 拮抗作用/NPFF 部分激动作用。此外，EKR 和 RKE 可完全阻断 NPFF 受体介导的 Neuro 2A 细胞的神经突生长。体内镇痛研究发现，EKR 和 RKE 的鞘内给药通过尾闪烁试验中的μ-阿片受体剂量依赖性地产生有效的镇痛作用。在角叉菜胶炎症性疼痛模型中，EKR 和 RKE 的脊髓给药诱导与剂量相关的镇痛作用，该作用被阿片拮抗剂纳洛酮和 NPFF 拮抗剂 RF9 显著减弱。值得注意的是，与吗啡相比，EKR 和 RKE 经脑室重复给药可维持较长时间的镇痛效果。此外，在这些具有镇痛作用的剂量下，这两种分支肽模拟物对胃肠道转运没有明显的抑制作用。总之，本研究表明，EKR 和 RKE 作为具有阿片激动作用和 NPFF 拮抗作用/NPFF 部分激动作用的多功能配体，可产生长效镇痛作用，且副作用有限。此外，我们的结果表明，EKR 和 RKE 可能是研究 NPFF 和阿片系统生物学功能的有趣的药理学工具。
