Rizzi A, Sukhtankar D D, Ding H, Hayashida K, Ruzza C, Guerrini R, Calò G, Ko M C
Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Br J Pharmacol. 2015 Jul;172(14):3661-70. doi: 10.1111/bph.13150. Epub 2015 May 12.
Using an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT2-N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer-lasting effects. The aim of the present study was to investigate the spinal effects of PWT2-N/OFQ in nociceptive and neuropathic pain models in mice and non-human primates.
Tail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2-N/OFQ were assessed in these models.
PWT2-N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non-human primates displaying 40-fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2-N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB-612111, but not to opioid receptor antagonists.
The present study has demonstrated that PWT2-N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non-human primates acting as a potent and longer-lasting NOP-selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.
采用一种创新的化学方法，即肽焊接技术（PWT），制备了一种四分支的孤啡肽/孤啡肽FQ（N/OFQ）衍生物，并对其进行了药理学表征。体外和体内实验中，PWT2-N/OFQ均表现出与天然配体相同的药理学特征。它的效力更强，作用持续时间更长。本研究的目的是在小鼠和非人类灵长类动物的伤害性疼痛和神经性疼痛模型中，研究PWT2-N/OFQ的脊髓效应。
小鼠和猴子的甩尾试验被用作伤害性疼痛模型，慢性压迫损伤小鼠的机械阈值被用作神经性疼痛模型。在这些模型中评估脊髓注射N/OFQ和PWT2-N/OFQ的镇痛作用。
在小鼠和非人类灵长类动物的伤害性疼痛和神经性疼痛模型中，PWT2-N/OFQ均模拟了N/OFQ的脊髓镇痛作用，其效力高40倍，作用持续时间明显延长。N/OFQ和PWT2-N/OFQ的作用对N/OFQ受体（NOP）拮抗剂SB-612111敏感，但对阿片受体拮抗剂不敏感。
本研究表明，PWT2-N/OFQ在啮齿动物和非人类灵长类动物中模拟了天然肽的镇痛作用，作为一种强效且作用持久的NOP选择性激动剂。更一般地说，生物活性肽的PWT衍生物可被视为用于研究那些选择性和延长受体刺激促进有益作用的病症和状态的创新药理学工具。
