Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Pharmacol Exp Ther. 2013 Jul;346(1):11-22. doi: 10.1124/jpet.113.203984. Epub 2013 May 7.
Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate μ-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1-(2,3,3α,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.
孤啡肽/强啡肽 FQ 肽受体（NOP）激动剂经脊髓给药后在动物模型中产生镇痛作用，并增强 μ 阿片受体（MOP）介导的镇痛作用。本研究确定了脊髓内给予双功能 NOP/MOP 配体的镇痛作用以及脊髓 NOP 和 MOP 受体在小鼠中的镇痛功能。双功能 NOP/MOP 配体 BU08028[（2S）-2-[[（5R，6R，7R，14S）-N-环丙基甲基-4，5-环氧-6，14-乙叉-3-羟基-6-甲氧基吗啡喃-7-基]-3，3-二甲基戊-2-醇]和 SR16435[1-（1-（2,3,3α,4,5,6-六氢-1H-苯并[a]萘-1-基）哌啶-4-基）-吲哚啉-2-酮]的药理学与假定的双功能配体丁丙诺啡、选择性 NOP 激动剂 SCH221510[3-endo-8-[双（2-甲基苯基）甲基]-3-苯基-8-氮杂双环[3.2.1]辛烷-3-醇]和选择性 MOP 激动剂吗啡在神经病理性和炎症性疼痛模型中进行了比较。此外，还确定了重复鞘内给予 SR16435 和丁丙诺啡后对其抗痛觉过敏作用的耐受性发展程度。我们的数据表明，BU08028 和 SR16435 比吗啡和 SCH221510 更能减弱神经损伤引起的触觉过敏和炎症引起的热痛觉过敏。受体选择性拮抗剂的共同给药进一步表明，脊髓中的 NOP 和 MOP 均介导了 BU08028 和 SR16435 的抗痛觉过敏作用，但鞘内丁丙诺啡诱导的抗痛觉过敏作用主要由 MOP 介导。与丁丙诺啡相比，重复鞘内给予 SR16435 导致其抗痛觉过敏作用的耐受性降低和发展缓慢。总之，脊髓中的 NOP 和 MOP 受体独立地驱动小鼠的镇痛作用。脊髓内给予的双功能 NOP/MOP 配体不仅能有效减轻神经病理性和炎症性疼痛，而且具有更高的镇痛效力，对镇痛的耐受性发展降低。因此，这些配体作为脊髓镇痛药具有良好的应用前景。
