The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys.
The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys.
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DOI：
10.1016/j.pbb.2022.173394
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发表时间：
2022-06
影响因子：
3.6
通讯作者：
Freeman, Kevin B.
中科院分区：
文献类型：
--
作者：
Huskinson, Sally L.;Platt, Donna M.;Zamarripa, C. Austin;Dunaway, Kristen;Brasfield, Morgan;Prisinzano, Thomas E.;Blough, Bruce E.;Freeman, Kevin B.
κ-阿片受体（KOR）激动剂已被研究作为疼痛、瘙痒和物质使用障碍的潜在治疗，但原型KOR激动剂产生如烦躁和镇静的副作用。已经报道了在KOR处表现出G蛋白偏向信号传导的非典型KOR激动剂产生治疗样作用，相对于原型KOR激动剂具有更少或减少的副作用。在本报告中，使用行为评分系统确定行为特征，该系统经过修改以量化非人灵长类动物（NHP）中的药物诱导行为。测定了原型和两种偏向性KOR激动剂单独使用和与μ阿片受体（莫尔）激动剂羟考酮联合使用的曲线。向5只植入静脉导管的成年雄性恒河猴单独施用一系列剂量的KOR激动剂U 50 - 488 H（0.01-0.1 mg/kg）和偏向性KOR激动剂纳呋拉芬（0.0001-0.001 mg/kg）和三唑1.1（0.32-1.0 mg/kg），以及与莫尔激动剂羟考酮（0.01-0.32 mg/kg）联合施用。此外，在时间过程测定（0-56分钟）中单独和与羟考酮（0.1 mg/kg）组合施用最大的测试的三唑1.1剂量（1.0 mg/kg）。U 50 - 488 H和纳呋拉芬产生镇静样和运动障碍作用。三唑1.1具有较轻的副作用特征，在某些情况下产生镇静样作用，但与其他KOR激动剂相比程度较低，特别是对于嘴唇下垂和休息/睡眠姿势。所有KOR激动剂都能减少羟考酮诱导的抓痕，但纳呋拉芬与羟考酮联合使用时产生了行为破坏和镇静样作用，而三唑1.1未观察到这些作用。三唑1.1的行为效应的持续时间相对较短，完全消散56分钟。我们的研究结果表明，与三唑1.1药理学相当的KOR激动剂可能是有用的治疗方法，副作用减少，这些好处的机制可能归因于G蛋白偏倚以外的因素。
Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side-effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50–488H (0.01–0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.32–1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01–0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0–56 min), alone and combined with oxycodone (0.1 mg/kg). U50–488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1’s behavioral effects were relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.
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影响因子：
3.4
作者：
Butelman, Eduardo R.;Rus, Szymon;Kreek, Mary Jeanne
通讯作者：
Kreek, Mary Jeanne
影响因子：
2.4
作者：
NOVAK, MA;ONEILL, P;SUOMI, SJ
通讯作者：
SUOMI, SJ
影响因子：
3.4
作者：
Platt, DM;Rowlett, JK;Ma, CR
通讯作者：
Ma, CR
影响因子：
3.2
作者：
Rueedi-Bettschen, Daniela;Rowlett, James K.;Platt, Donna M.
通讯作者：
Platt, Donna M.
DOI：
10.1124/jpet.118.249250
发表时间：
2018-07-01
影响因子：
3.5
作者：
Duke, Angela N.;Meng, Zhiqiang;Rowlett, James K.
通讯作者：
Rowlett, James K.