Department of Morphology, Surgery and Experimental Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, Italy.
Department of Medical Sciences, Section of Pharmacology, National Institute of Neuroscience, University of Ferrara, Italy.
Neuropharmacology. 2020 Jul;171:108110. doi: 10.1016/j.neuropharm.2020.108110. Epub 2020 Apr 25.
MT-45 is a synthetic opioid that was developed in the 1970s as an analgesic compound. However, in recent years MT-45 has been associated with multiple deaths in Europe and has been included in the class of novel psychoactive substances known as novel synthetic opioids (NSOs). Little is known about the pharmaco-toxicological effects of MT-45. Therefore, we used a dynamic mass redistribution (DMR) assay to investigate the pharmacodynamic profile of this NSO in vitro compared with morphine. We then used in vivo studies to investigate the effect of the acute systemic administration of MT-45 (0.01-15 mg/kg i.p.) on motor and sensorimotor (visual, acoustic and tactile) responses, mechanical and thermal analgesia, muscle strength and body temperature in CD-1 male mice. Higher doses of MT-45 (6-30 mg/kg i.p.) were used to investigate cardiorespiratory changes (heart rate, respiratory rate, SpO saturation and pulse distention). All effects of MT-45 were compared with those of morphine. In vitro DMR assay results demonstrated that at human recombinant opioid receptors MT-45 behaves as a potent selective mu agonist with a slightly higher efficacy than morphine. In vivo results showed that MT-45 progressively induces tail elevation at the lowest dose tested (0.01 mg/kg), increased mechanical and thermal antinociception (starting from 1 to 6 mg/kg), decreased visual sensorimotor responses (starting from 3 to 6 mg/kg) and reduced tactile responses, modulated motor performance and induced muscle rigidity at higher doses (15 mg/kg). In addition, at higher doses (15-30 mg/kg) MT-45 impaired the cardiorespiratory functions. All effects were prevented by the administration of the opioid receptor antagonist naloxone. These findings reveal the risks associated with the ingestion of opioids and the importance of studying these drugs and undertaking more clinical studies of the current molecules to better understand possible therapeutic interventions in the case of toxicity.
MT-45 是一种合成阿片类药物，于 20 世纪 70 年代作为一种镇痛药化合物开发。然而，近年来 MT-45 已在欧洲与多起死亡事件有关，并被纳入新型精神活性物质类，即新型合成阿片类物质（NSO）。关于 MT-45 的药物毒理学效应知之甚少。因此，我们使用动态质量重分布（DMR）测定法来研究这种 NSO 在体外与吗啡的药效学特征。然后，我们使用体内研究来研究 MT-45（0.01-15 mg/kg，ip）急性全身给药对 CD-1 雄性小鼠运动和感觉运动（视觉、听觉和触觉）反应、机械和热镇痛、肌肉力量和体温的影响。使用较高剂量的 MT-45（6-30 mg/kg，ip）来研究心肺变化（心率、呼吸频率、SpO 饱和度和脉搏扩张）。将 MT-45 的所有作用与吗啡的作用进行比较。体外 DMR 测定结果表明，在人源重组阿片受体中，MT-45 表现为一种强效选择性μ激动剂，其效力略高于吗啡。体内结果表明，MT-45 在最低测试剂量（0.01 mg/kg）下逐渐引起尾巴抬高，增加机械和热镇痛（从 1 至 6 mg/kg），降低视觉感觉运动反应（从 3 至 6 mg/kg）和触觉反应，调节运动性能并在较高剂量（15 mg/kg）下引起肌肉僵硬。此外，在较高剂量（15-30 mg/kg）下，MT-45 会损害心肺功能。阿片受体拮抗剂纳洛酮的给药可预防所有这些作用。这些发现揭示了摄入阿片类药物的风险，以及研究这些药物并对当前分子进行更多临床研究的重要性，以便在毒性情况下更好地了解可能的治疗干预措施。
