Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632, USA.
J Pharmacol Exp Ther. 2012 Oct;343(1):72-81. doi: 10.1124/jpet.112.194308. Epub 2012 Jun 28.
Buprenorphine is known as a μ-opioid peptide (MOP) receptor agonist, but its antinociception is compromised by the activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine-induced physiological responses in primates (rhesus monkeys). The effects of MOP antagonist (naltrexone), NOP antagonist [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397)], and NOP agonists [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one (Ro 64-6198) and 3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)] on buprenorphine were studied in three functional assays for measuring analgesia, respiratory depression, and itch in primates. Over the dose range of 0.01 to 0.1 mg/kg, buprenorphine dose-dependently produced antinociception, respiratory depression, and itch/scratching responses, and there was a ceiling effect at higher doses (0.1-1 mg/kg). Naltrexone (0.03 mg/kg) produced similar degrees of rightward shifts of buprenorphine's dose-response curves for all three endpoints. Mean pK(B) values of naltrexone (8.1-8.3) confirmed that MOP receptors mediated mainly buprenorphine-induced antinociception, respiratory depression, and itch/scratching. In contrast, J-113397 (0.1 mg/kg) did not change buprenorphine-induced physiological responses, indicating that there were no functional NOP receptors in buprenorphine-induced effects. More importantly, both NOP agonists, Ro 64-6198 and SCH 221510, enhanced buprenorphine-induced antinociception without respiratory depression and itch/ scratching. The dose-addition analysis revealed that buprenorphine in combination with the NOP agonist synergistically produced antinociceptive effects. These findings provided functional evidence that the activation of NOP receptors did not attenuate buprenorphine-induced antinociception in primates; instead, the coactivation of MOP and NOP receptors produced synergistic antinociception without other side effects. This study strongly supports the therapeutic potential of mixed MOP/NOP agonists as innovative analgesics.
丁丙诺啡被认为是一种μ-阿片肽（MOP）受体激动剂，但在啮齿动物中，其镇痛作用会受到孤啡肽/孤啡肽 FQ 肽（NOP）受体的激活的影响。本研究旨在探讨 MOP 和 NOP 受体在调节灵长类动物（恒河猴）中丁丙诺啡诱导的生理反应中的作用。研究了 MOP 拮抗剂（纳曲酮）、NOP 拮抗剂[（±）-1-[(3R*，4R*）-1-（环辛基甲基）-3-（羟甲基）-4-哌啶基]-3-乙基-1,3-二氢-2H-苯并咪唑-2-酮（J-113397）]和 NOP 激动剂[（1S，3aS）-8-（2,3,3a,4,5,6-六氢-1H-菲伦-1-基）-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-4-酮（Ro 64-6198）和 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（SCH 221510）]对丁丙诺啡的影响，这三种功能测定方法用于测量灵长类动物的镇痛、呼吸抑制和瘙痒。在 0.01 至 0.1 mg/kg 的剂量范围内，丁丙诺啡剂量依赖性地产生镇痛、呼吸抑制和瘙痒/搔抓反应，高剂量（0.1-1 mg/kg）时出现天花板效应。纳曲酮（0.03 mg/kg）对所有三个终点的丁丙诺啡剂量反应曲线产生了相似程度的右移。纳曲酮的平均 pK（B）值（8.1-8.3）证实 MOP 受体主要介导丁丙诺啡诱导的镇痛、呼吸抑制和瘙痒/搔抓。相比之下，J-113397（0.1 mg/kg）未改变丁丙诺啡诱导的生理反应，表明丁丙诺啡诱导的作用中没有功能性 NOP 受体。更重要的是，两种 NOP 激动剂，Ro 64-6198 和 SCH 221510，增强了丁丙诺啡诱导的镇痛作用，而没有呼吸抑制和瘙痒/搔抓。剂量相加分析显示，丁丙诺啡与 NOP 激动剂联合使用可协同产生镇痛作用。这些发现提供了功能证据，表明 NOP 受体的激活并没有减弱灵长类动物中丁丙诺啡诱导的镇痛作用；相反，MOP 和 NOP 受体的共同激活产生了协同的镇痛作用，而没有其他副作用。这项研究强烈支持混合 MOP/NOP 激动剂作为创新镇痛剂的治疗潜力。
