µ opioid receptor agonism for L-DOPA-induced dyskinesia in Parkinson’s disease
J. Neurosci.. 2020-07-20; : JN-RM-0610-20
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Bezard E(1)(2)(3)(4), Li Q(3)(4), Hulme H(5)(6), Fridjonsdottir E(5), Nilsson A(5)(6), Pioli E(3), Andren PE(5)(6), Crossman AR(3).
(1)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France .
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
(3)Motac Neuroscience, Manchester, M15 6WE, United Kingdom.
(4)Institute of Lab Animal Sciences, China Academy of Medical Sciences, 100021 Beijing, China.
(5)Medical Mass Spectrometry Imaging, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-75124 Uppsala, Sweden.
(6)Science for Life Laboratory, National Resource for Mass Spectrometry Imaging, Uppsala University, Box 591, SE-75124 Uppsala, Sweden.
Parkinson’s disease (PD) is characterized by severe locomotor deficits and is
commonly treated with the dopamine precursor L-DOPA, but its prolonged usage
causes dyskinesias referred to as L-DOPA induced dyskinesia (LID). Several
studies in animal models of PD have suggested that dyskinesias are associated
with a heightened opioid co-transmitter tone, observations that have led to the
notion of a LID-related hyperactive opioid transmission that should be corrected
by µ opioid receptor antagonists. Reports that both antagonists and agonists of
the µ opioid receptor may alleviate LID severity in primate models of PD and LID,
together with the failure of non-specific antagonist to improve LID in pilot
clinical trials in patients, raises doubt about the reliability of the available
data on the opioid system in PD and LID. After in vitro characterization of the
functional activity at the µ opioid receptor, we selected prototypical agonists,
antagonists and partial agonists at the µ opioid receptor. We then showed that
both oral and discrete intracerebral administration of a µ receptor agonist, but
not of an antagonist as long thought, ameliorated LIDs in the gold-standard
bilateral MPTP-lesioned female macaque model of PD and LID. The results call for
a re-appraisal of opioid pharmacology in the basal ganglia as well as for the
development of brain nucleus-targeted µ opioid receptor agonists.SIGNIFICANCE
STATEMENTµ opioid receptors have long been considered as a viable target for
alleviating the severity of L-DOPA-induced hyperkinetic side-effects, induced by
the chronic treatment of Parkinson’s disease motor symptoms with L-DOPA.
Conflicting results between experimental parkinsonism and PD patients, however,
dampened the enthusiasm for the target. Here we reappraise the pharmacology and
then demonstrate that both oral and discrete intracerebral administration of a µ
receptor agonist, but not of an antagonist as long thought, ameliorates LIDs in
the gold-standard bilateral MPTP-lesioned macaque model of Parkinson’s disease,
calling for a re-appraisal of the opioid pharmacology as well as for the
development of brain nucleus-targeted µ receptor agonists.