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: 1.22). 12/2005; 11(11):BR397-404.
Source: PubMed

ABSTRACT 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, Aug 14, 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.
    Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology 01/2015; 169. DOI:10.1016/j.cbpc.2014.12.006 · 2.83 Impact Factor
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    • "Finally, additional data from our group indicates an approximate 3-fold enhancement of tissue concentrations of endogenous morphine following administration of THP to an ex vivo preparation of invertebrate ganglia (Zhu et al., 2005b). The observed rate of conversion of THP to morphine of approximately 20 % when compared to the low steady-state levels of tissue THP suggested high intrinsic clearance of THP and other morphine precursors through a defined cellular biosynthetic pathway. "
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    ABSTRACT: For over 30 years empirical studies have repeatedly demonstrated that the biosynthesis of morphine by diverse animal and human tissues occurs. Recently, the blue mussel's neural tissues and human white blood cells were used to demonstrate the de novo biosynthesis of morphine for small precursor molecules derived from the aromatic amino acid L-tyrosine. Because catecholamine precursors, i.e., L-3,4-dihydroxyphenylalanine (L-DOPA), were also found to be utilized as morphine precursors, a novel reciprocally interactive mechanism is apparent that links catecholamine and opioid pathways in the activation and inhibition of diverse tissue responses. Additionally, these observations provide new insights into morphinergic signalling that transcend analgesia and addiction. We have also linked the biological effects of nitric oxide into a common effect in endogenous morphine signalling. Given the singular importance of dopamine and morphine's interaction in the CNS, the presence and association of this signalling with nitric oxide all promises to provide novel answers for mental health phenomena, which have been lacking because of the inability in accepting the empirical endogenous morphine studies.
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    • "Taken together, these studies provide evidence that the synthesis of morphine by various tissues and diverse animals is more widespread than previously thought and now includes human immune cells and potentially human stem cells. Importantly, morphine biosynthesis uses elements of the catecholamine pathway as precursor molecules in its synthesis, such as tyrosine, L-DOPA and dopamine , suggesting that their modulation is critical for endogenous morphinergic processes (Kream & Stefano 2006; Zhu et al 2005b; 2005c). Furthermore, cholinergic nicotinic processes has also been shown to be involved with endogenous morphine processes via novel nicotinic receptors, which can modulate cellular morphine release into its microenvironment (Zhu et al 2006b; 2006c; 2006d; 2006e; 2007; 2008). "
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    ABSTRACT: Human white blood cells (WBC) and stem cells were treated with morphine and total RNA from these cells was analyzed using the Human Genome Survey microarray (Applied Biosystems). WBC nicotinic receptor gene expression, including variants, were down regulated. In general, of the 57 pre-selected neurotransmitter-related genes, only 11 changed significantly. Only 2 genes were up regulated, dopamine receptor 3 and cholin-ergic receptor, nicotinic, gamma polypeptide. The remaining 9 genes were down regulated, 5 in WBC and 4 in stem cells. The dopamine receptor D4 was the only gene that was commonly modulated in both cell types. It was down regulated by approx. 200% in stem cells and by 50% in WBC. The genes that exhibited the greatest extent of down regula-tion were 5-hydroxytryptamine receptor 3A in WBC and prepronociceptin in stem cells. Acetylcholinesterase, tyrosine hydroxylase, proenkephalin and dopamine receptor 3 were among the genes only found in WBC, whereas collagen-like tail subunit -single strand of homotrimer-of asymmetric acetylcholinesterase, dopamine receptor 1 and the serotonin transporter SLC6A4, were among those genes expressed only in stem cells. The genes for multiple sub-types of cholinergic receptors were lacking in stem cells. Thus, differential expression of genes was evident as well as specific morphine effects on gene expression, suggesting that morphine effects other neurotransmitter systems.
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