MP1104, a mixed kappa-delta opioid receptor agonist has anti-cocaine properties with reduced side-effects in rats
MP1104, a mixed kappa-delta opioid receptor agonist has anti-cocaine properties with reduced side-effects in rats
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DOI：
10.1016/j.neuropharm.2019.02.010
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发表时间：
2019-05-15
影响因子：
4.7
通讯作者：
Kivell, Bronwyn M.
中科院分区：
文献类型：
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作者：
Atigari, Diana V.;Uprety, Rajendra;Kivell, Bronwyn M.
Kappa阿片受体(KOPr)激动剂具有临床前抗可卡因和抗伤害作用。然而，包括烦躁、厌恶、镇静、焦虑和抑郁在内的不良反应限制了它们的临床发展。MP1104是3-碘苯甲酰纳曲胺的类似物，是KOPr和Delta阿片受体(DOPR)的双重激动剂，对这两种受体都有完全的激动剂作用。在这项研究中，我们评估了MP1104在临床前调节可卡因诱导的行为和副作用的能力。在接受自我给药训练的雄性SD大鼠中，MP1104(0.3和1 mg/kg)降低了可卡因诱导的寻求行为的恢复，并使可卡因自我给药试验的剂量-反应曲线显著下移(0.3和0.6 mg/kg)。MP1104的抗可卡因作用部分是由于背侧纹状体(DSTR)和伏核(NAC)的多巴胺转运体(DAT)摄取多巴胺(DA)。MP1104(0.3和0.6 mg/kg)在高架迷宫和强迫游泳实验中无明显的抗焦虑作用，在强迫游泳实验中无明显的抑制作用，在条件性位置厌恶实验中无明显的抑制作用。此外，用DOPR拮抗剂预处理会导致MP1104产生厌恶效应。这一数据表明，MP1104的DOPR激动剂作用减弱了KOPr介导的MP1104的厌恶效应。这项研究的总体结果表明，与纯KOPr激动剂相比，MP1104调节DSTR和NAC中的DA摄取，并在自我给药测试中发挥强大的抗可卡因特性，副作用减少。这些数据支持双KOPr/DOPR激动剂的治疗开发，以减少选择性KOPr激动剂的副作用。这篇文章是题为《阿片类神经药理学：治疗疼痛和阿片成瘾的进展》特刊的一部分。
Kappa opioid receptor (KOPr) agonists have preclinical anti-cocaine and antinociceptive effects. However, adverse effects including dysphoria, aversion, sedation, anxiety and depression limit their clinical development. MP1104, an analogue of 3-iodobenzoyl naltrexamine, is a potent dual agonist at KOPr and delta opioid receptor (DOPr), with full agonist efficacy at both these receptors. In this study, we evaluate the ability of MP1104 to modulate cocaine-induced behaviors and side-effects preclinically. In male Sprague-Dawley rats trained to self-administer cocaine, MP1104 (0.3 and 1 mg/kg) reduced cocaine-primed reinstatement of drug-seeking behavior and caused significant downward shift of the dose-response curve in cocaine self-administration tests (0.3 and 0.6 mg/kg). The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine (DA) uptake by the dopamine transporter (DAT) in the dorsal striatum (dStr) and nucleus accumbens (NAc). MP1104 (0.3 and 0.6 mg/kg) showed no significant anxiogenic effects in the elevated plus maze, pro-depressive effects in the forced swim test, or conditioned place aversion. Furthermore, pretreatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. The overall results from this study show that MP1104, modulates DA uptake in the dStr and NAc, and exerts potent anti-cocaine properties in self-administration tests with reduced side-effects compared to pure KOPr agonists. This data supports the therapeutic development of dual KOPr/DOPr agonists to reduce the side-effects of selective KOPr agonists.This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.