Usefulness for the combination of G-protein- and β-arrestin-biased ligands of μ-opioid receptors: Prevention of antinociceptive tolerance.
Usefulness for the combination of G-protein- and β-arrestin-biased ligands of μ-opioid receptors: Prevention of antinociceptive tolerance.
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DOI：
10.1177/1744806917740030
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发表时间：
2017-01
期刊：
影响因子：
3.3
通讯作者：
Narita M
中科院分区：
文献类型：
--
作者：
Mori T;Kuzumaki N;Arima T;Narita M;Tateishi R;Kondo T;Hamada Y;Kuwata H;Kawata M;Yamazaki M;Sugita K;Matsuzawa A;Baba K;Yamauchi T;Higashiyama K;Nonaka M;Miyano K;Uezono Y;Narita M
μ-阿片受体内化被认为与抗伤害耐受性密切相关。尽管μ-阿片受体激动剂已与其他药物同时给药以控制疼痛，但关于阿片-阿片相互作用的信息很少。因此，本研究旨在进一步研究一种新的G蛋白偏向的μ-阿片受体配体TRV 130的效用，TRV 130具有抗伤害作用，而没有β-arrestin依赖的μ-阿片受体内化，以及它与芬太尼的组合使用μ-阿片受体表达细胞和小鼠。在本研究中，我们证实芬太尼引起β-arrestin-2募集的显著增加，伴随着μ-阿片受体内化，而TRV 130在μ-阿片受体表达细胞中既不诱导β-arrestin-2的募集，也不诱导μ-阿片受体内化。在这些条件下，TRV 130消除了芬太尼诱导的β-arrestin-2募集伴随着μ-阿片受体内化，而TRV 130没有改变μ-阿片受体表达细胞中芬太尼减少环磷酸腺苷形成的情况。在行为测定中，TRV 130在小鼠的热板试验中发挥抗伤害感受作用。在组合试验中，TRV 130的抗伤害感受作用被芬太尼协同增加。坐骨神经结扎后神经病理性疼痛样状态下芬太尼诱导的抗痛觉过敏及其耐受性的发展。然而，在神经性疼痛样状态下，用抗伤害剂量的TRV 130治疗小鼠并没有诱导对其抗痛觉过敏作用的耐受性的快速发展。此外，在坐骨神经结扎的小鼠中，未观察到对芬太尼加TRV 130诱导的抗痛觉过敏作用的耐受性的快速发展，这与单独使用芬太尼的情况不同。这些发现提供了证据表明，通过μ-阿片受体激活G蛋白偏向通路可以改变与μ-阿片受体刺激相关的β-arrestin-2通路中的信号传导。此外，μ-阿片受体的G蛋白偏向性和β-arrestin偏向性配体的组合发挥了理想的抗伤害性作用，而不会迅速产生抗伤害性耐受。
µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid–opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for µ-opioid receptors, TRV130, which has an antinociceptive effect without β-arrestin-dependent µ-opioid receptor internalization, and its combination with fentanyl using µ-opioid receptor-expressing cells and mice. In the present study, we confirmed that fentanyl produced a profound increase in β-arrestin-2 recruitment accompanied by µ-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of β-arrestin-2 or µ-opioid receptor internalization in µ-opioid receptor-expressing cells. Under these conditions, β-arrestin-2 recruitment accompanied by µ-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cyclic adenosine monophosphate formation by fentanyl in µ-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development of its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. These findings provide evidence that activation of the G protein-biased pathway through µ-opioid receptors can alter signaling in the β-arrestin-2 pathway linked to the stimulation of µ-opioid receptors. Furthermore, the combination of G protein-biased and β-arrestin-biased ligands of µ-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.
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影响因子：
8.8
作者：
Hayhurst, Christina J.;Durieux, Marcel E.
通讯作者：
Durieux, Marcel E.
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
7.4
作者：
SELTZER, Z;DUBNER, R;SHIR, Y
通讯作者：
SHIR, Y
在类似神经病理性疼痛的状态下，脊髓μ-阿片受体脱敏时间的延长可能参与了μ-阿片类药物抗过敏耐受性的形成。
影响因子：
3.4
作者：
Narita M;Imai S;Nakamura A;Ozeki A;Asato M;Rahmadi M;Sudo Y;Hojo M;Uezono Y;Devi LA;Kuzumaki N;Suzuki T
通讯作者：
Suzuki T
影响因子：
13.8
作者：
Cahill CM;Walwyn W;Taylor AMW;Pradhan AAA;Evans CJ
通讯作者：
Evans CJ