Endogenous morphine and its metabolites in mammals: History, synthesis, localization and perspectives (original) (raw)
Related papers
2012
Positive evolutionary pressure has apparently preserved the ability to synthesize chemically authentic morphine, albeit in homeopathic concentrations, throughout animal phyla. Despite the establishment of a progressively rigorous and mechanistically focused historical literature extending from the mid 1970s to the mid 1980s that supported the expression of chemically authentic morphine by animal cellular and organ systems, prejudicial scepticism and early dismissal by scientists and clinicians most often obscured widespread acceptance of the biological importance and medical implications of endogenous morphine. The current critical paper presents and evaluates key recent coordinated studies in endogenous morphine research, highlighting those that have advanced our understanding of the functional roles of cognate alkaloid-selective μ3 and μ4 opiate receptors. We propose that the expression of endogenous morphine by animal and human cells is designed to mediate homeopathic regulation ...
Morphine's chemical messenger status in animals
2009
Conventional wisdom recognizes morphine only as a plant product with profound pharmacological actions on mammalian tissues. This widely held belief ignores 30 years of empirical evidence from different laboratories, demonstrating its presence and synthesis in animal tissues, including human. Using state-of-the-art technologies, we recently demonstrated that normal healthy animal tissues, including human, have the ability to synthesize morphine in a process that both resembles that occurring in plants and one which is subject to pharmacological manipulation via existing mammalian enzymes. Importantly, this ability also occurs in invertebrate neural tissues in animals 500 million years divergent in evolution. Morphine is present in human immune, vascular and neural tissues, along with its own receptor, µ3, which we have cloned and found to be opioid peptide insensitive and opiate alkaloid selective, establishing its endogenous signaling capabilities. The functional implications of endogenous morphine expression as a parallel, but independently regulated signaling system, confers a major adaptive advantage to an expanding cadre of L-tyrosine-derived molecular species as autocrine, paracrine, and hormonal regulators of cellular systems involved in immune function, neural-immune coupling in the mediation of nociception and antinociception, and cardiovascular integrity linked to functional recruitment of constitutive nitric oxide (NO). These linkages are the driving knowledge that now supports a role for intracellular morphine expression and its biosynthetic intermediates as developmental chaperones in the evolutionary adaptation of dopamine and its catecholamine derivatives norepinephrine and epinephrine as signaling molecules.
The Presence of Endogenous Morphine Signaling in Animals
Neurochemical Research, 2008
Recent empirical findings have contributed valuable mechanistic information in support of a regulated de novo biosynthetic pathway for chemically authentic morphine and related morphinan alkaloids within animal cells. Importantly, we and others have established that endogenously expressed morphine represents a key regulatory molecule effecting local circuit autocrine/paracrine cellular signaling via a novel l 3 opiate receptor coupled to constitutive nitric oxide production and release. The present report provides an integrated review of the biochemical, pharmacological, and molecular demonstration of l 3 opiate receptors in historical linkage to the elucidation of mechanisms of endogenous morphine production by animal cells and organ systems. Ongoing research in this exciting area provides a rare window of opportunity to firmly establish essential biochemical linkages between dopamine, a morphine precursor, and animal biosynthetic pathways involved in morphine biosynthesis that have been conserved throughout evolution.
Central and peripheral endogenous morphine
Morphine was first identified in opium from Papaver somniferum, and is still one of the strongest known analgesic compounds used in hospital. Since the beginning of the 80s, endogenous morphine, with an identical structure to that of morphine isolated from poppies, has been characterised in numerous mammalian cells and tissues. In mammals, the biosynthesis of endogenous morphine is associated with dopamine, as demonstrated in the SH-SY5Y human neuronal catecholamine-producing cell line. More recently, morphine and morphine-6-glucuronide has been shown to be present in the human neuroblastoma SH-SY5Y cell line and that morphine is secreted from the large dense core vesicles in response to nicotine stimulation via a Ca 2+-dependent mechanism suggesting its implication in neurotransmission. An increasing number of publications have demonstrated its presence and implication in different biological processes at the central and peripheral levels. The present review reports the major data concerning endogenous morphine presence and implication in physiological processes.
Comparative Aspects of Endogenous Morphine Synthesis and Signaling in Animals
Annals of the New York Academy of Sciences, 2009
For many years it has been believed that animals cannot make morphine. However, within the last 30 years scientific documents have emerged reporting on endogenous animal opiate synthesis, including morphine biosynthesis in animals and specific tissues. These data are complemented by other reports demonstrating the presence of opiate receptors specifically used for morphinergic signaling in animal tissues, bringing together the lock-and-key concept for an animal morphine chemical messenger hypothesis.
Morphine: New aspects in the study of an ancient compound
Life Sciences, 1994
Morphine is the most widely used compound among narcotic analgesics and remains the gold standard when the effects of other analgetic drugs are compared. Apart from its presence in the poppy plant Papaver somniferum, morphine has been shown to be present in milk, cerebrospinal fluid and also in nervous tissue extracts. Recent evidence suggests that biosynthetic pathways for morphine exist in animal and even human tissues such as liver, blood and brain. The most characteristic effect of morphine is the modulation of pain perception resulting in an increase in the threshold of noxious stimuli. Antinociception induced by morphine is mediated via opioid receptors and therefore can be inhibited by opioid antagonists, e.g., naloxone. Nevertheless, consideration of morphine as endogenous ligand for opioid receptors seems to be speculative. Recently, the primary receptor for morphine-type drugs called the la-opioid receptor has been cloned from rat brain. There is accumulating evidence that morphine actions are, at least partly, due to one of its major metabolite morphine-6-glucuronide in man. It is concluded that further investigations are necessary to elucidate the mechanisms, whereby multiple actions of morphine are expressed in the nervous system.
The Journal of Comparative Neurology, 2011
Endogenous morphine, morphine-6-glucuronide, and codeine, which are structurally identical to vegetal alkaloids, can be synthesized by mammalian cells from dopamine. However, the role of brain endogenous morphine and its derivative compounds is a matter of debate, and knowledge about its distribution is lacking. In this study, by using a validated antibody, we describe a precise mapping of endogenous morphine-like compounds (morphine and/ or its glucuronides and/or codeine) in the mouse brain. First, a mass spectrometry approach confirmed the presence of morphine and codeine in mouse brain, but also, of morphine-6-glucuronide and morphine-3-glucuronide representing two metabolites of morphine. Second, light microscopy allowed us to observe immunopositive cell somas and cytoplasmic processes throughout the mouse brain. Morphine-like immunoreactivity was present in various structures including the hippocampus, olfactory bulb, band of Broca, basal ganglia, and cerebellum. Third, by using confocal microscopy and immunofluroscence co-localization, we characterized cell types containing endogenous opiates. Interestingly, we observed that morphine-like immunoreactivity throughout the encephalon is mainly present in c-aminobutyric acid (GABA)ergic neurons. Astrocytes were also labeled throughout the entire brain, in the cell body, in the cytoplasmic processes, and in astrocytic feet surrounding blood vessels. Finally, ultrastructural localization of morphine-like immunoreactivity was determined by electron microscopy and showed the presence of morphinelike label in presynaptic terminals in the cerebellum and postsynaptic terminals in the rest of the mouse brain. In conclusion, the presence of endogenous morphine-like compounds in brain regions not usually involved in pain modulation opens the exciting opportunity to extend the role and function of endogenous alkaloids far beyond their analgesic functions.