Parkinson’s disease, L-DOPA, and endogenous morphine: A revisit

Abstract

SummaryClinical observations stemming from widespread employment of restorative L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for management of dyskinesia in Parkinson’s Disease (PD) patients implicate a regulatory role for endogenous morphine in central nervous system dopamine neurotransmission. Reciprocally, it appears that restorative L-DOPA administration has provided us with a compelling in vivo pharmacological model for targeting peripheral sites involved in endogenous morphine expression in human subjects. The biological activities underlying endogenous morphine expression and its interaction with its major precursor dopamine strongly suggest that endogenous morphine systems are reciprocally dysregulated in PD. These critical issues are examined from historical and current perspectives within our short review.

The Neuroprotection of Low-Dose Morphine in Cellular and Animal Models of Parkinson’s Disease Through Ameliorating Endoplasmic Reticulum (ER) Stress and Activating Autophagy

“…Previous study demonstrated endogenous morphine presents in human SH-SY5Y neuroblastoma cell line ( Muller et al, 2008 ), which is often used for PD study in vitro . Stefano et al (2012) reported endogenous morphine biosynthesis was dysregulated in PD. The key enzymes for endogenous morphine biosynthesis include CYP2D6 , CYP3A4 and CYP3A5 .…”

“…Moreover, dopamine is demonstrated to be the precursor for endogenous morphine biosynthesis ( Stefano et al, 2008 ). Intriguingly, previous study indicated that endogenous morphine systems were reciprocally dysregulated in PD ( Stefano et al, 2012 ). Together, these studies indicated low level of endogenous morphine may be protective for neurodegenerative disease, particular PD.…”

“…Thus, these results indicated that morphine produced either detrimental or protective effects in the CNS and the effects of morphine may be dependent on the dosage and exposure time. Interestingly, compelling evidence demonstrated that endogenous morphine exists and is biosynthesized in the CNS ( Guarna et al, 2005 ) and is able to regulate dopaminergic neurotransmission ( Stefano et al, 2012 ). Moreover, dopamine is demonstrated to be the precursor for endogenous morphine biosynthesis ( Stefano et al, 2008 ).…”

Usos terapéuticos potenciales de los antagonistas opioides: Fisiopatología y evidencia preclínica

“…ej., µ y δ) incrementan los niveles de dopamina en el núcleo accumbens [70], no resulta improbable que el sistema opioide pueda ser un blanco terapéutico para pacientes con enfermedad de Parkinson. Estudios mediante imágenes funcionales en humanos [71], así como en modelos animales [72], indican una desregulación del sistema opioide en la enfermedad de Parkinson (EP), así como mecanismos compensatorios generados por dicho sistema en los ganglios basales que pueden explicar parte de la fisiopatología de la enfermedad [73]. No hay evidencia del uso de antagonistas opioides para el manejo de la EP; sin embargo, en el caso de la disquinesia inducida por levodopa [74], estudios en primates indican una mejoría clínica con el uso de antagonistas específicos para µ (cyprodime) y δ (naltrindole), sin afectar los efectos antiparkinsonianos de la misma levodopa [75], lo cual podría tener utilidad clínica para el manejo de las reacciones adversas de pacientes tratados con levodopa a largo plazo.…”

Pentazocine Protects SN4741 Cells Against MPP+-Induced Cell Damage via Up-Regulation of the Canonical Wnt/β-Catenin Signaling Pathway

“…Elyasi et al ( 2014 ) reported that morphine can protect the SH-SY5Y human neuroblastoma cells against 6-OHDA-induced cell damage. The biological activities underlying opioid production strongly indicated that opioid production systems are reciprocally dysregulated in PD models (Stefano et al, 2012 ). Opioids, a class of compounds including morphine and pentazocine, may have neuroprotective effects and act as a promising therapy for neurodegeneration disease.…”