Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia

Rita L. Vaz, Diana Chapela, Joana E. Coelho, Luísa V. Lopes, Joaquim J. Ferreira, Nuno D. Afonso, Sara Sousa, Tiago F. Outeiro

Research output: Contribution to journalArticle

Abstract

The motor features in Parkinson's disease (PD) are associated with the degeneration of dopaminergic cells in the substantia nigra in the brain. Thus, the gold-standard in PD therapeutics still consists of dopamine replacement with levodopa. However, as the disease progresses, this therapeutic option becomes less effective and can be accompanied by levodopa-induced complications. On the other hand, several other neuronal pathways have been implicated in the pathological mechanisms of PD. In this context, the development of alternative therapeutic options that modulate non-dopaminergic targets is emerging as a major goal in the field. In a phenotypic-based screen in a zebrafish model of PD, we identified tapentadol as a candidate molecule for PD. The therapeutic potential of an agent that modulates the opioid and noradrenergic systems has not been explored, despite the implication of both neuronal pathways in parkinsonism. Therefore, we assessed the therapeutic properties of this µ-opioid receptor agonist and norepinephrine reuptake inhibitor in the 6-hydroxydopamine mouse model of parkinsonism. We further submitted 6-hydroxydopamine-lesioned mice to chronic treatment with levodopa and evaluated the effects of tapentadol during levodopa OFF states and on levodopa-induced dyskinesia. Importantly, we found that tapentadol halted the aggravation of dyskinesia and improved the motor impairments during levodopa OFF states. Altogether, our findings raise the hypothesis that concomitant modulation of µ-opioid receptor and norepinephrine transporter might constitute relevant intervention strategies in PD and that tapentadol holds therapeutic potential that may be translated into the clinical practice.

Original languageEnglish
Pages (from-to)58-71
Number of pages14
JournalNeuroscience
Volume424
DOIs
Publication statusPublished - 2020

Fingerprint

Dyskinesias
Levodopa
Parkinson Disease
Oxidopamine
Parkinsonian Disorders
Opioid Receptors
Therapeutics
Norepinephrine Plasma Membrane Transport Proteins
Zebrafish
Substantia Nigra
Gold
Opioid Analgesics
tapentadol
Dopamine
Norepinephrine
Brain

Keywords

  • levodopa-induced dyskinesia
  • mouse
  • norepinephrine reuptake inhibitor
  • Parkinson's disease
  • tapentadol
  • µ-opioid receptor agonist

Cite this

Vaz, R. L., Chapela, D., Coelho, J. E., Lopes, L. V., Ferreira, J. J., Afonso, N. D., ... Outeiro, T. F. (2020). Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia. Neuroscience, 424, 58-71. https://doi.org/10.1016/j.neuroscience.2019.08.046
Vaz, Rita L. ; Chapela, Diana ; Coelho, Joana E. ; Lopes, Luísa V. ; Ferreira, Joaquim J. ; Afonso, Nuno D. ; Sousa, Sara ; Outeiro, Tiago F. / Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia. In: Neuroscience. 2020 ; Vol. 424. pp. 58-71.
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Vaz, RL, Chapela, D, Coelho, JE, Lopes, LV, Ferreira, JJ, Afonso, ND, Sousa, S & Outeiro, TF 2020, 'Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia', Neuroscience, vol. 424, pp. 58-71. https://doi.org/10.1016/j.neuroscience.2019.08.046

Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia. / Vaz, Rita L.; Chapela, Diana; Coelho, Joana E.; Lopes, Luísa V.; Ferreira, Joaquim J.; Afonso, Nuno D.; Sousa, Sara; Outeiro, Tiago F.

In: Neuroscience, Vol. 424, 2020, p. 58-71.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia

AU - Vaz, Rita L.

AU - Chapela, Diana

AU - Coelho, Joana E.

AU - Lopes, Luísa V.

AU - Ferreira, Joaquim J.

AU - Afonso, Nuno D.

AU - Sousa, Sara

AU - Outeiro, Tiago F.

PY - 2020

Y1 - 2020

N2 - The motor features in Parkinson's disease (PD) are associated with the degeneration of dopaminergic cells in the substantia nigra in the brain. Thus, the gold-standard in PD therapeutics still consists of dopamine replacement with levodopa. However, as the disease progresses, this therapeutic option becomes less effective and can be accompanied by levodopa-induced complications. On the other hand, several other neuronal pathways have been implicated in the pathological mechanisms of PD. In this context, the development of alternative therapeutic options that modulate non-dopaminergic targets is emerging as a major goal in the field. In a phenotypic-based screen in a zebrafish model of PD, we identified tapentadol as a candidate molecule for PD. The therapeutic potential of an agent that modulates the opioid and noradrenergic systems has not been explored, despite the implication of both neuronal pathways in parkinsonism. Therefore, we assessed the therapeutic properties of this µ-opioid receptor agonist and norepinephrine reuptake inhibitor in the 6-hydroxydopamine mouse model of parkinsonism. We further submitted 6-hydroxydopamine-lesioned mice to chronic treatment with levodopa and evaluated the effects of tapentadol during levodopa OFF states and on levodopa-induced dyskinesia. Importantly, we found that tapentadol halted the aggravation of dyskinesia and improved the motor impairments during levodopa OFF states. Altogether, our findings raise the hypothesis that concomitant modulation of µ-opioid receptor and norepinephrine transporter might constitute relevant intervention strategies in PD and that tapentadol holds therapeutic potential that may be translated into the clinical practice.

AB - The motor features in Parkinson's disease (PD) are associated with the degeneration of dopaminergic cells in the substantia nigra in the brain. Thus, the gold-standard in PD therapeutics still consists of dopamine replacement with levodopa. However, as the disease progresses, this therapeutic option becomes less effective and can be accompanied by levodopa-induced complications. On the other hand, several other neuronal pathways have been implicated in the pathological mechanisms of PD. In this context, the development of alternative therapeutic options that modulate non-dopaminergic targets is emerging as a major goal in the field. In a phenotypic-based screen in a zebrafish model of PD, we identified tapentadol as a candidate molecule for PD. The therapeutic potential of an agent that modulates the opioid and noradrenergic systems has not been explored, despite the implication of both neuronal pathways in parkinsonism. Therefore, we assessed the therapeutic properties of this µ-opioid receptor agonist and norepinephrine reuptake inhibitor in the 6-hydroxydopamine mouse model of parkinsonism. We further submitted 6-hydroxydopamine-lesioned mice to chronic treatment with levodopa and evaluated the effects of tapentadol during levodopa OFF states and on levodopa-induced dyskinesia. Importantly, we found that tapentadol halted the aggravation of dyskinesia and improved the motor impairments during levodopa OFF states. Altogether, our findings raise the hypothesis that concomitant modulation of µ-opioid receptor and norepinephrine transporter might constitute relevant intervention strategies in PD and that tapentadol holds therapeutic potential that may be translated into the clinical practice.

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KW - norepinephrine reuptake inhibitor

KW - Parkinson's disease

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Vaz RL, Chapela D, Coelho JE, Lopes LV, Ferreira JJ, Afonso ND et al. Tapentadol Prevents Motor Impairments in a Mouse Model of Dyskinesia. Neuroscience. 2020;424:58-71. https://doi.org/10.1016/j.neuroscience.2019.08.046