Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents.
Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents.
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DOI：
10.1177/0269881116689257
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Negus SS
中科院分区：
文献类型：
--
作者：
Altarifi AA;David B;Muchhala KH;Blough BE;Akbarali H;Negus SS
TRV 130（oliceridine; N-[（3-甲氧基噻吩-2-基）甲基]-2-[（9 R）-9-吡啶-2-基-6-氧杂螺[4.5]癸烷-9-基]乙胺）是一种新型μ阿片受体（莫尔）激动剂，其优先激活G-蛋白相对于与MOR偶联的β-抑制蛋白信号传导途径。现有的证据表明，TRV 130和其他G蛋白偏向的莫尔激动剂可以产生治疗性镇痛作用，与现有的莫尔激动剂相比，副作用减少。本研究比较了急性和重复TRV 130给药对啮齿动物的抗伤害感受、胃肠道功能和滥用倾向的影响。我们假设TRV 130在重复治疗期间将产生稳健和持续的抗伤害感受和滥用相关作用，但耐受性将发展为GI抑制。在小鼠中使用温水尾部撤回程序评估抗伤害感受。使用粪便排出量的体内测量和结肠推进以及结肠和回肠环形肌肉收缩的体外测定来评估小鼠的胃肠功能。使用颅内自我刺激（ICSS）程序评估大鼠的滥用倾向。（+）-TRV 130以急性和重复给药方案给药，并且还在ICSS程序中检查（−）-TRV 130以评估立体选择性。急性（+）-TRV 130治疗产生了强大的抗伤害感受，完全抑制胃肠道功能，和弱滥用相关的影响。重复（+）-TRV 130治疗未能产生耐受性的抗伤害或GI抑制，滥用相关的影响，通过重复治疗增强。急性和重复的（+）-TRV 130在这些程序中的作用类似于吗啡的作用，除了TRV 130抗伤害感受对耐受性更有抗性。（-）-TRV 130无活性。这些结果表明，TRV 130在重复治疗期间保留了不期望的便秘和滥用相关作用，尽管其对G蛋白信号传导的偏好。
TRV130 (oliceridine; N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine) is a novel mu opioid receptor (MOR) agonist that preferentially activates G-protein vs. β-arrestin signaling pathways coupled to MORs. Prevailing evidence suggests that TRV130 and other G-protein-biased MOR agonists may produce therapeutic analgesic effects with reduced adverse effects compared to existing MOR agonists. This study compared effects of acute and repeated TRV130 administration on measures of antinociception, gastrointestinal function, and abuse liability in rodents. We hypothesized that TRV130 would produce robust and sustained antinociception and abuse-related effects during repeated treatment, but that tolerance would develop to GI inhibition. Antinociception was assessed using a warm-water tail-withdrawal procedure in mice. Gastrointestinal function was assessed in mice using an in vivo measure of fecal output and in vitro assays of colonic propulsion and of colon and ileum circular muscle contraction. Abuse liability was assessed in rats using an intracranial self-stimulation (ICSS) procedure. (+)-TRV130 was administered with acute and repeated dosing regimens, and (−)-TRV130 was also examined in the ICSS procedure to assess stereoselectivity. Acute (+)-TRV130 treatment produced robust antinociception, complete inhibition of gastrointestinal function, and weak abuse-related effects. Repeated (+)-TRV130 treatment failed to produce tolerance to antinociception or GI inhibition, and abuse-related effects were enhanced by repeated treatment. Effects of acute and repeated (+)-TRV130 in these procedures resemble effects of morphine, with the exception that TRV130 antinociception was more resistant to tolerance. (−)-TRV130 was inactive. These results suggest that TRV130 retains undesirable constipating and abuse-related effects during repeated treatment despite its bias for G-protein signaling.
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作者：
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