Micheli Laura, Di Cesare Mannelli Lorenzo, Lucarini Elena, Parisio Carmen, Toti Alessandra, Fiorentino Bruno, Rigamonti Maria Adele, Calosi Laura, Ghelardini Carla
Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
Molteni Farmaceutici S.p.A, Florence, Italy.
Front Pharmacol. 2020 Sep 18;11:576624. doi: 10.3389/fphar.2020.576624. eCollection 2020.
Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the clinical practice. Unfortunately, together with analgesia, a number of adverse effects can occur such as nausea, vomiting, constipation, gastrointestinal alterations and cognitive impairments. Naltrexone is a competitive antagonist of opioid receptors commonly used to treat opioid addiction; its oral use against agonists side effects is limited by the decrease of opioids-therapeutic efficacy and own adverse effects. The intranasal delivery of naltrexone could offer a quick and effective achievement of CNS based on extracellular mechanisms including perineural and perivascular transport. The aim of the study was to test the efficacy of intranasal low-dose naltrexone in reducing intraperitoneal morphine and oxycodone side effects in rodents. In mice, 1 μg naltrexone intranasally administered 30 min before opioids reduced cognitive impairments and motor alteration induced by 10 mg kg morphine and 60 mg kg oxycodone in the Passive avoidance and Rota rod tests, respectively. Moreover, naltrexone rebalanced opioid-induced reduction of the intestinal transit and latency of feces expulsion as well as food intake inhibition. Importantly, 1 μg naltrexone instillation did not block analgesia as demonstrated by the Hot plate test. In rats, intranasal naltrexone counteracted the opioid-induced pica phenomenon related to emesis and increased water and palatable food intake. The effects were comparable to that achieved by metoclopramide used as reference drug. Treatments did not influence body weight. Lastly, the safety of the intranasal delivery has been checked by hematoxylin-eosin staining that did not show histological alterations of the nasal cavity. In conclusion, intranasal low-dose naltrexone counteracted morphine and oxycodone induced gastrointestinal and CNS side effects without impairing opioid analgesia. It is a candidate to be a valid clinical strategy deserving deep analysis.
阿片类药物是广谱镇痛药，是临床实践中对抗疼痛的治疗手段不可或缺的一部分。不幸的是，与镇痛作用同时出现的是，可能会发生一些不良反应，如恶心、呕吐、便秘、胃肠道改变和认知障碍。纳曲酮是一种阿片受体竞争性拮抗剂，常用于治疗阿片类药物成瘾；其口服用于对抗激动剂副作用时，会因阿片类药物治疗效果降低和自身不良反应而受到限制。纳曲酮的鼻内给药可基于包括神经周围和血管周围转运在内的细胞外机制快速有效地作用于中枢神经系统。本研究的目的是测试鼻内低剂量纳曲酮在减轻啮齿动物腹腔注射吗啡和羟考酮副作用方面的疗效。在小鼠中，在给予阿片类药物前30分钟鼻内给予1μg纳曲酮，分别在被动回避试验和转棒试验中减轻了10mg/kg吗啡和60mg/kg羟考酮诱导的认知障碍和运动改变。此外，纳曲酮恢复了阿片类药物引起的肠道转运减少、粪便排出延迟以及食物摄入抑制。重要的是，如热板试验所示，1μg纳曲酮滴鼻并未阻断镇痛作用。在大鼠中，鼻内纳曲酮抵消了与呕吐相关的阿片类药物诱导的异食癖现象，并增加了水和美味食物的摄入量。这些效果与用作参考药物的甲氧氯普胺所达到的效果相当。治疗对体重没有影响。最后，通过苏木精-伊红染色检查了鼻内给药的安全性，结果未显示鼻腔组织学改变。总之，鼻内低剂量纳曲酮抵消了吗啡和羟考酮引起的胃肠道和中枢神经系统副作用，而不损害阿片类药物的镇痛作用。它是一种值得深入分析的有效临床策略的候选药物。
