Morphine: New aspects in the study of an ancient compound (original) (raw)
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Neuroscience, 2013
Morphine derived from Papaver somniferum is commonly used as an analgesic compound for pain relief. It is now accepted that endogenous morphine, structurally identical to vegetal morphine-alkaloid, is synthesized by mammalian cells from dopamine. Morphine binds mu opioid receptor and induces antinociceptive effects. However, the exact role of these compounds is a matter of debate although different links with infection, sepsis, inflammation, as well as major neurological pathologies (Parkinson's disease, schizophrenia) have been proposed. The present review describes endogenous morphine and morphine derivative discovery, synthesis, localization and potential implications in physiological and pathological processes.
British Journal of Pharmacology, 1992
The emetic potencies of morphine and its metabolite morphine 6-glucuronide have been determined in the ferret by constructing dose-response curves for mean total retches and vomits for subcutaneous doses of 0.05 mg kg-' to 5 mg kg-'. Morphine 6-glucuronide induced retching and vomiting at lower doses than morphine and at a maximal dose induced more retching and vomiting than morphine. 2 The emesis induced by both morphine and morphine 6-glucuronide was abolished by the preadministration of naloxone (0.5 mg kg-' s.c.). 3 The 5-HT3 receptor antagonists granisetron and ondansetron (1 mg kg-', s.c.) failed to abolish or reduce emesis induced by either compound. 4 At a high-dose (5 mg kg-'), morphine but not morphine 6-glucuronide failed to induce emesis and abolished the emesis induced by the cytotoxic drug, cyclophosphamide (200mgkg-', i.p.). 5 Preliminary pharmacokinetic studies of intravenous and subcutaneous morphine and morphine 6-glucuronide revealed that morphine 6-glucuronide accounts for less than 1% of the metabolic product of morphine in the ferret. Peak plasma levels of the two compounds after their subcutaneous administration were obtained within 10min. The metabolic profile of morphine was not dose-dependent. There was no relationship between plasma level and emetic response for either compound.
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.
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.
Receptors for morphine and opioids
General Pharmacology: The Vascular System, 1976
Two points concerning enzymatic systems acting on disposal of morphine are discussed, namely the multiplicity of glucuronyltransferase and the effect of nalorphine on N-demethylation of morphine.
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 ...
Medical science monitor : international medical journal of experimental and clinical research, 2005
Morphine-6beta-glucuronide (M6G), a metabolite of morphine that the brain can produce, is an opiate agonist that appears to have a greater analgesic potency than morphine. M6G has a 1-octanol/water partition coefficient 187 times lower than that of morphine and M6G has a blood brain barrier permeability 57 times lower than morphine. The brain uptake rate however is only 32 times lower, suggesting that an active transport mechanism might be present. Furthermore, evidence for a distinct receptor for M6G also appears to be emerging. Real time polymerase chain reactions allowed for the discovery of single nucleotide polymorphisms (SNP's) in the human mu opioid receptor gene. The most common SNP is a substitution at base118 where A is replaced with G (A118G). This SNP has a decreased potency for M6G in individuals possessing it whereas the potency of morphine is unaffected by this SNP. The possibility that a peripheral opiate signaling system, using M6G and its distinct receptor, exi...
Effects of morphine glucuronides on the function of opioid receptors in human SK-N-SH cells
Neuroscience Letters, 2000
Morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are active metabolites of morphine. The effects of M3G and M6G on the opioid receptor transduction system has not yet been fully elucidated. Formation of cAMP after treatment with various doses of morphine, M3G, and M6G was studied. M6G and morphine, but not M3G, showed a dose dependent inhibition of cAMP accumulation. Naloxone blocked the inhibitory effect of M6G, M3G, and morphine. Pretreatment with M3G did not change the effects of morphine and M6G. The G-protein inhibitor PTX, prevented morphine, M3G, and M6G effects on cAMP. M3G and M6G vary in their ability to interact with the opioid receptor effector system. Inhibition of cAMP evoked by activation of opioid receptors and inhibitory G-proteins may play a role in the actions of M6G and M3G. q