The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats.
The G-protein biased mu-opioid agonist, TRV130, produces reinforcing and antinociceptive effects that are comparable to oxycodone in rats.
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DOI：
10.1016/j.drugalcdep.2018.08.002
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发表时间：
2018-11-01
影响因子：
4.2
通讯作者：
Freeman KB
中科院分区：
文献类型：
--
作者：
Austin Zamarripa C;Edwards SR;Qureshi HN;Yi JN;Blough BE;Freeman KB
μ-阿片激动剂（例如，羟考酮）是高度有效的疼痛治疗剂。然而，它们也产生强化作用，增加了被滥用的可能性。最近的药物开发策略集中在阿片类药物上，这些阿片类药物具有偏向的受体信号传导特征，这些特征有利于激活特定的细胞内途径，目的是增加治疗选择性。TRV 130是一种偏向G蛋白信号传导的μ激动剂，其产生的抗伤害作用与μ激动剂吗啡相当，但副作用减少。然而，就滥用潜力而言，我们知道没有已发表的临床前数据调查TRV 130作为药物的作用。在本研究中，我们评估了TRV 130和羟考酮（一种常用的μ受体激动剂）在大鼠中的相对强化作用，这些大鼠在强化的渐进比（PR）时间表下自我给药。此外，我们在热抗伤害感受试验（热板）中评估了TRV 130和羟考酮在大鼠中的相对效力和功效。对于自我给药，雄性Sprague-Dawley大鼠（n=7）在强化的递增比（PR）方案下自我静脉内输注TRV 130或羟考酮（0.01-0.32 mg/kg/inj）。对于热板试验，雄性大鼠（n=7）接受TRV 130（0.1-3.2 mg/kg/inj）或羟考酮（0.1-5.6 mg/kg/inj）的皮下注射，并测量伤害感受性反应潜伏期。TRV 130和羟考酮在自我给药和热抗伤害感受方面是等效的。这项研究表明，TRV 130产生的增强和抗伤害作用在数量上与羟考酮相似，并且偏倚信号传导特征不一定会降低滥用潜力。
Mu-opioid agonists (e.g., oxycodone) are highly effective therapeutics for pain. However, they also produce reinforcing effects that increase their likelihood of abuse. Recent strategies in drug development have focused on opioids with biased receptor-signaling profiles that favor activation of specific intracellular pathways over others with the aim of increasing therapeutic selectivity. TRV130, a mu-agonist biased towards G-protein signaling, produces antinociceptive effects comparable to the mu-agonist, morphine, but exhibits reduced side effects. However, in terms of abuse potential, we know of no published preclinical data investigating the effects of TRV130 as a reinforcer. In the present study, we assessed the relative reinforcing effects of TRV130 and oxycodone, a commonly-prescribed mu-agonist, in rats self-administering the drugs under a progressive-ratio (PR) schedule of reinforcement. In addition, we assessed the relative potency and efficacy of TRV130 and oxycodone in rats in a test of thermal antinociception (Hot Plate). For self-administration, male Sprague-Dawley rats (n=7) self-administered intravenous infusions of TRV130 or oxycodone (0.01–0.32 mg/kg/inj) under a progressive-ratio (PR) schedule of reinforcement. For the Hot-Plate Test, male rats (n=7) received subcutaneous injections of TRV130 (0.1–3.2 mg/kg/inj) or oxycodone (0.1–5.6 mg/kg/inj), and nociceptive response latencies were measured. TRV130 and oxycodone were equi-potent and equi-effective in selfadministration and thermal antinociception. This study demonstrates that TRV130 produces reinforcing and antinociceptive effects that are quantitatively similar to oxycodone, and that a biased-signaling profile does not necessarily reduce abuse potential.
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DOI：
10.1007/bf00421261
发表时间：
1975-01-01
期刊：
PSYCHOPHARMACOLOGIA
影响因子：
--
作者：
KOOB, GF;SPECTOR, NH;MEYERHOFF, JL
通讯作者：
MEYERHOFF, JL
mu 阿片受体 G 蛋白偏向激活和失活机制的计算见解
影响因子：
8.2
作者：
Cheng, Jian-xin;Cheng, Tao;Tang, Yun
通讯作者：
Tang, Yun
影响因子：
64.8
作者：
Matthes, HWD;Maldonado, R;Kieffer, BL
通讯作者：
Kieffer, BL
影响因子：
56.9
作者：
Bohn, LM;Lefkowitz, RJ;Lin, FT
通讯作者：
Lin, FT
影响因子：
4
作者：
Siuda, Edward R.;Carr, Richard, III;Violin, Jonathan D.
通讯作者：
Violin, Jonathan D.