Nociceptin receptor antagonist

我们目前的研究表明，由一种名为nociceptin或orphaninFQ的新型生物活性肽介导的神经调节调节了包括疼痛、学习记忆和听力在内的几种信号传递途径。基于我们的研究结果，这项合作研究的目的是(i)试图识别伤害感受素受体的拮抗剂化合物，（ii）在整个动物水平上检查这些化合物作为强效镇痛药或记忆刺激剂，以及进一步（iii）分析伤害感受素系统神经调节的生理作用。我们的合作团队成员成功地发现化合物NalBenzH和J-113397选择性地作为nociceptin受体的拮抗剂。在我们的初步研究中，比较了这些化合物在缺乏痛觉肽受体的野生型小鼠和突变型小鼠之间的药理反应，它们似乎产生了微弱的镇痛作用。然而，为了检验它们作为广泛疼痛或记忆刺激剂的强效镇痛药的可能性，我们需要计划进一步的动物水平研究。另一方面，我们的合作研究明确了痛觉肽前体蛋白和痛觉肽受体在中枢神经系统中的表达模式、痛觉肽在脊髓背角的突触传递调控、痛觉肽系统在吗啡耐受和依赖获得过程中的作用以及痛觉肽介导的物质介导的痛觉肽诱导的疼痛反应。

Our current studies have suggested that neuro-modulations mediated by the novel bioactive peptide named nociceptin or orphaninFQ regulate several signal-transmission pathways including pain, learning and memory and hearing. Based on our results, aims of this collaborative study were (i) attempt to identify chemical compounds acting antagonists for the nociceptin receptor, (ii) examination of such compounds as potent analgesics or memory stimulants in the whole animal level, and further (iii) analysis of physiological roles of neuro-modulations by the nociceptin system.Members in our collaborative team successfully found that chemical compounds, NalBenzH and J-113397, act as antagonists selectively for the nociceptin receptor. In our preliminary study comparing pharmacological responses of the compounds between wild-typec mice and mutant mice lacking the nociceptin receptor, they seemed to produce weak analgesic effects. However, to examine the possibility that they can be potent analgesics for broad- ranged pains or memory stimulants, we need to plan further animal-level studies. On the other hand, our collaborative studies have clarified the expression patterns of both the nociceptin precursor protein and nociceptin receptor in the central nervous system, the modulation of synaptic transmission by nociceptin in the dorsal horn of the spinal cord, the role of the nociceptin system during acquirement of morphine tolerance and dependence, and the nociceptin-mediated regulation of substanceP-induced pain responses.