Cippitelli Andrea, Zribi Gilles, Toll Lawrence
Biomedical Science Department, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States.
Biomedical Science Department, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2022 Dec 20;119:110599. doi: 10.1016/j.pnpbp.2022.110599. Epub 2022 Jul 5.
Cocaine use disorder (CUD) is a persistent public health problem for which no effective medications are available. PPL-103 is an opioid receptor ligand with partial agonist activity at mu, kappa and delta opioid receptors, with a greater efficacy for kappa and low efficacy at mu receptors. Because chronic cocaine use induces changes in the kappa opioid receptor/dynorphin system, we hypothesized that a kappa partial agonist, such as PPL-103, would attenuate the aversive properties of the upregulated kappa system, resulting in effective treatment approach for CUD. We tested the effects of PPL-103 on cocaine self-administration models that recapitulate core aspects of CUD in humans. We found that PPL-103 reduced both long and short access cocaine self-administration, motivation to respond for cocaine, and binge-like cocaine taking, in rats. Operant responding for food, fentanyl and locomotor behavior were not altered at doses that decreased cocaine infusions. Repeated PPL-103 treatment did not lead to tolerance development. PPL-103 also reduced both priming- and cue-induced reinstatement of cocaine seeking, being more effective in the former. Surprisingly, PPL-103 reduced self-administration parameters and reinstatement in rats previously treated with the long-acting kappa receptor antagonist JDTic more potently than in non-JDTic treated animals, whereas naltrexone injected to rats subsequent to JDTic administration increased self-administration, suggesting that the partial mu agonist activity, rather than kappa agonism is important for reduction in cocaine taking and seeking. However, partial kappa activation seems to increase safety by limiting dysphoria, tolerance and addiction development. PPL-103 displays a desirable profile as a possible CUD pharmacotherapy.
可卡因使用障碍（CUD）是一个持续存在的公共卫生问题，目前尚无有效的药物治疗。PPL-103是一种阿片受体配体，对μ、κ和δ阿片受体具有部分激动剂活性，对κ受体的效力更强，对μ受体的效力较低。由于长期使用可卡因会导致κ阿片受体/强啡肽系统发生变化，我们推测κ部分激动剂，如PPL-103，会减弱上调的κ系统的厌恶特性，从而产生治疗CUD的有效方法。我们测试了PPL-103对可卡因自我给药模型的影响，该模型概括了人类CUD的核心特征。我们发现，PPL-103减少了大鼠长期和短期的可卡因自我给药、对可卡因反应的动机以及类似暴饮暴食的可卡因摄取。在降低可卡因注射量的剂量下，对食物、芬太尼的操作性反应和运动行为没有改变。重复给予PPL-103治疗不会导致耐受性的产生。PPL-103还减少了引发和线索诱导的可卡因觅药行为的恢复，对前者更有效。令人惊讶的是，PPL-103在先前用长效κ受体拮抗剂JDTic治疗的大鼠中比未用JDTic治疗的动物更有效地降低了自我给药参数和觅药行为的恢复，而在JDTic给药后给大鼠注射纳曲酮会增加自我给药，这表明部分μ激动剂活性而非κ激动作用对于减少可卡因摄取和觅药行为很重要。然而，部分κ激活似乎通过限制烦躁不安、耐受性和成瘾的发展来提高安全性。PPL-103作为一种可能的CUD药物疗法显示出理想的特性。
