In vitro and in vivo pharmacological characterization of the synthetic opioid MT-45

NEUROPHARMACOLOGY

卷:171

Article

Bilel, S.^1,2  Azevedo, N. J.³  Arfe, R.^1,2,4  Tirri, M.^1,2  Gregori, A.⁶  Serpelloni, G.⁷  De-Giorgio, F.^4,5  Frisoni, P.^1,2  Neri, M.^1,2  Calo, G.³  Marti, M.^1,2,8 

[1] Univ Ferrara, Sect Legal Med, Dept Morphol Surg & Expt Med, Via Fossato Mortara 70, I-44121 Ferrara, Italy

[2] Univ Ferrara, LTTA Ctr, Ferrara, Italy

[3] Univ Ferrara, Natl Inst Neurosci, Dept Med Sci, Sect Pharmacol, Ferrara, Italy

[4] Univ Cattolica Sacro Cuore, Inst Publ Hlth, Sect Legal Med, Rome, Italy

[5] Fdn Policlin Univ A Gemelli IRCCS, Rome, Italy

[6] Dept Sci Invest RIS, Carabinieri, I-00191 Rome, Italy

[7] Univ Florida, Dept Psychiat, Drug Policy Inst, Coll Med, Gainesville, FL 32611 USA

[8] Presidency Council Minist, Collaborat Ctr Natl Early Warning Syst, Dept Antidrug Policies, Rome, Italy

关键词: MT-45;    Morphine;    Naloxone;    DMR assay;    Novel psychoactive substances;    Synthetic opioids;   

DOI  :  10.1016/j.neuropharm.2020.108110

来源: Elsevier

【 摘 要 】

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(2) 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.

【 授权许可】

Free