Tyrosine and tyramine increase endogenous ganglionic morphine and dopamine levels in vitro and in vivo: Cyp2d6 and tyrosine hydroxylase modulation demonstrates a dopamine coupling

Neuroscience Research Institute, State University of New York, College at Old Westbury, New York 11568, USA.
Medical science monitor: international medical journal of experimental and clinical research (Impact Factor: 1.43). 12/2005; 11(11):BR397-404.
Source: PubMed


The ability of animals to make morphine has been in question for the last 30 years. Studies have demonstrated that animals do contain morphine precursors and metabolites, as well as the ability to use some morphine precursors to make morphine.
The present study uses excised ganglia from the marine invertebrate Mytilus edulis as well as whole animals. Morphine and dopamine levels were determined by high performance liquid chromatography coupled to electrochemical detection and radioimmunoassay. Tissues and whole animals were also exposed to morphine precursors and exposed to the CYP2D6 inhibitor quinidine and the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). Additionally, via RT-PCR, a cDNA fragment of the CYP2D6 enzyme in the ganglia of M. edulis was identified.
Pedal ganglia incubated with either tyramine or tyrosine, or whole animals receiving injections, exhibited a statistically significant concentration- and time-dependent increase in their endogenous morphine and dopamine levels (2.51 +/- 0.76 ng/g for tyrosine and 2.39 +/- 0.64 ng/g for tyramine compared to approximately 1.0 ng/g morphine wet weight). Incubation with quinidine and/or AMPT diminished ganglionic morphine and dopamine synthesis at various steps in the synthesis process. We also demonstrated that CYP2D6 mediates the tyramine to dopamine step in this process, as did tyrosine hydroxylase in the step from tyrosine to L-DOPA. Furthermore, via RT-PCR, we identified a cDNA fragment of the CYP2D6 enzyme in the ganglia, which exhibits 94% sequence identity with its human counterpart. Evidence that tyrosine and tyramine were, in part, being converted to dopamine then morphine, and that this process can be inhibited by altering either or both CYP2D6 or tyrosine hydroxylase, is also provided.
It appears that animals have the ability to make morphine. This process also appears to be dynamic in that the inhibition of one pathway allows the other to continue with morphine synthesis. Moreover, dopamine and morphine synthesis were coupled.

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Available from: Tobias Esch, Oct 10, 2015
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    • "Tyrosine is a non-essential amino acid that serves as substrate precursor for the synthesis of catecholamines, which include adrenaline, noradrenaline, and dopamine. The conversion of tyrosine into catecholamines is catalyzed by the enzyme tyrosine hydroxylase (TH), involved in the adrenergic–dopaminergic system that, in Mytilus, has an inhibitory effect on lateral cilia beating (Zhu et al., 2005). TH is a mixed-function oxidase that uses molecular oxygen and tyrosine as its substrates, and biopterin as its cofactor (Shiman et al., 1971). "
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    ABSTRACT: The neurotoxicological potential of environmental pollution, mainly related to petrochemical activities, was investigated in marine mussel Mytilus galloprovincialis. Bivalve molluscs, particularly mussels, are widely used as sentinel organisms in biomonitoring studies for assessing the impact of anthropogenic contaminants. The gills, mainly involved in nutrient uptake, digestion, gas exchange and neuronal signaling, are the first organ to be affected by pollutants present in the external environment, and therefore were selected as target organ for this study. Mussels from an aquaculture farm were caged at a highly polluted petrochemical area and a reference site along the Augusta coastline (eastern Sicily, Italy) for one month. A battery of biomarkers indicative of neuronal perturbations was applied on gills in order to investigate on the serotoninergic (i.e. serotonin, 5-HT, and its receptor, 5-HT3R), cholinergic (i.e. acetylcholine, acetylcholinesterase, AChE, and choline acetyltransferase, ChAT), and dopaminergic system (i.e. tyrosine and tyrosine hydroxylase, TH). Overall, impairment in the normal ciliary motility was found in mussels caged at the polluted site. Alterations in serotoninergic and cholinergic systems were revealed, with enhancement of dopaminergic neurotransmission resulting in a cilio-inhibitory effect. However, the over-expression in 5-HT3R and ChAT at cellular level may indicate an adaptive response of mussels to recover a regular physiological activity in gills. To our knowledge, this is the first study that uses (1)H NMR and immunohistochemical assays. Their concurrent use demonstrated to be sensitive and effective for assessing environmental influences on the health status of aquatic organisms, and thus suitable to be applied in ecotoxicological studies. Copyright © 2014. Published by Elsevier Inc.
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    • "Specifically, endogenous morphine production has been demonstrated in limbic tissues, e.g., hippocampus and amygdala [42,43,88,89]. It is made by human and invertebrate cells [90,91] and dopamine serves as a major precursor, linking many of these phenomena (love, addiction, eating) into a “common” signaling family [87,92]. It’s presence in human stem cells underscores its importance in evolution as well as its persistence [92,93]. "
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    • "Whereas the cellular effects of 1% ethanol may be functionally linked to its anesthetic properties [21-25], a 100 fold lower concentration of 2 mM ethanol, equivalent to a non-activating, sensitizing, dose of 0.01% was observed to produce an effective doubling of 125I-trace labeled morphine released into the extracellular medium. Because DA and its immediate precursors L-TYR, L-DOPA, and TA also serve as biosynthetic intermediates in cellular morphine expression [26, 27], ethanol-mediated anesthetic inhibition of dopamine signaling may effectively divert excess precursor molecules to cellular morphine pools. "
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