Endogenous morphine

Endorphin An endogenous opiate neuropeptide (endogenous morphine). 

G.B. Stefano, W. Zhu, P. Cadet, T.V. Bilfinger, and K. Mantione, Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the mu 3 opiate receptor subtype a hormonal role for endogenous morphine. J. Physiol. Pharmacol. 55, 279-288 (2004). 

Mass spectrometry has been applied mainly in proteome research, but also in discovery and quantitation of neuropeptides that are involved in pain mechanisms, such as nocistatin, substance P, or verification of, for example, the structure of endogenous morphine in the central nervous system. Some proteomics studies of pain are aimed at the search for pain markers in cerebrospinal fluid, as it may reflect changes in brain and spinal cord functioning. Another research area concerns proteome analysis in cancer pain using spinal cord tissue and animal models. 

Naloxone will block the effects of opiate drugs and is used to treat overdoses. It was found that during trauma the use of naloxone would increase pain and prevent naturally induced analgesia. It was only a matter of time until the endogenous opiates, the endorphins (for endogenous morphine) and enkephalins, were discovered. Now there exists a whole nomenclature of opiate receptor types and their various effects. 

The effects of morphine eventually led many scientists to predict that the brain possesses its own endogenous opiate-like neurotransmitters and its own complement of endogenous opiate receptors in the brain. In the mid-i97o s research confirmed that the brain and body do indeed contain some endogenous morphine-like peptides and christenedthem endorphins. These peptides control our experience of pain by stopping the flow of pain signals into our brains, and this action is enhanced... 

The answer is yes. In the 1970s, scientists found that the brain produces morphine-like narcotics called endorphins (endogenous morphines) that activate the opiate receptors in the brain. Morphine also attaches to opiate receptors therefore, it is actually mimicking the effects of these human-produced endorphins that create the euphoria and reduction in pain often experienced by a morphine user. 

Morphine as a typical plant natural product has also been identified many times in animals and humans, initially leading to the belief that its occurrence is of a dietary origin or of de novo synthesis [93]. However, surprisingly, feeding experiments with labelled precursors to neuroblastome cells have recently provided clear evidence of the presence of endogenous morphine formation in human cells [94], Moreover, the finding that some of the morphine biosynthesis-specific enzymes are present in some of these cells provides the first, surprising, clear-cut evidence for its enzyme catalysed formation in non-plant cells [95, 96]. 

Endorphins are small neuropeptides that are produced by the body and act to reduce pain—hence, the name endorphin (a shortened version of endogenous morphine). The term enkephalin (meaning literally in the head ) is also applied to endorphins, but usually refers to smaller molecules that have pain-relieving properties. 

Subsequent conversion into heroin 2 was first reported in 1874 by Wright in the UK as a result of boiling morphine acetate the process was commercialised by Bayer AG in 1898. The subsequent use and abuse of these compounds is much too complex to discuss here, but one major discovery came in the early 1970s when Pert and Synder reported the identification of opioid receptors in brain tissue.17 This report was followed closely by the identification of endogenous morphine-like substances in 1975 by Kosterlitz and Hughes,18 which over the next few years led to the identification of enkephalins, endorphins and dynorphins—all of which had the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met/Leu), leading to the concept that morphine actually mimics this sequence.19... 

P-Endorphin is but one of an ever-increasing number of peptide neurotransmitters, and one of the rare cases in which there actually are specific agonists and antagonists - the name endorphin stands for endogenous morphine . 

The endogenous ligands for the opioid receptors are peptides known as the endorphins (endogenous morphine) or opio-peptins. These include the pentapep tides methionine-enkephalin and leucine-enkephalin and a hep tapep tide and octapeptide version of methionine-enkephalin, all derived from preproenkephalin p-endorphin derived from proopiomelanocortin a-and p-dynorphin derived from prodynorphin endomorphin-1 and -2, whose precursor has not been definitively identified and orphanin FQ or nociceptin, derived from OFQ/N precursor protein. These peptides are discussed in more detail in Chapter 34. 

The molecular structure of opioids is similar to that of certain neurotransmitters that occur naturally in the brain. Because of the similarities, these drugs are able to cross the blood-brain barrier and able to occupy receptor sites used by these neurotransmitters. The brain substances are called endorphins, which is short for endogenous morphines. The endorphins are what provide our natural pain control. 

Stefano GB, Goumon Y, Casares F, et al Endogenous morphine [review]. Trends Neurosci... 

The opioid peptides isolated from mammalian tissue are known collectively as endorphins, a word that is derived from a combination of endogenous and morphine. The opioid alkaloids and all of the synthetic opioid derivatives are exogenous opioids. Interestingly, the isolation of morphine and codeine in small amounts has been reported from mammalian brain (9). The functional significance of endogenous morphine remains unknown. 

Candace Pert, together with Solomon Snyder (Johns Hopkins, Baltimore, USA), first identified opioid receptors in the brain in 1972 (Figure 1.5). In 1975 Hans Kosterlitz and John Hughes (Aberdeen, UK) reported the existence of an endogenous morphine-like substance and named it enkephalin (for in the head ). Enkephalins, endorphins, and dynorphins bind to specific receptor sites in the brain. 

Alkaloids in mammals can be sequestered from vegetal or animal sources and are produced by the organism. It is known that morphine can be synthesized by mammalian cell from dopamine. This mammalian endogenous morphine is identical with vegetal morphine from Papaver somniferum It is empirically evidenced that human cells also can produce morphine. Exogenous alkaloids, depending on their bioactivities, can work in mammals in curative process of disorders and diseases and as hallucinogens or as poisons. Other mammalian alkaloids are well-known alkaloids such as beta-carbolines and isoquinolines. 

Laux-Biehlmann A, Mouheiche J, Veriepe J, Goumon Y. Endogenous morphine and its metabolites in mammals history, synthesis, localization and perspectives. Neuroscience 2013 233 95-117. 

Zhu W, Mantione KJ, Casares FM, Sheehan MH, Kream RM, Stefano GB. Cholinergic regulation of endogenous morphine release from lobster nerve cord. Med Sci Monit 2006 12(9) BR295-301. 

Recently, the endogenous morphine receptor ligand, enkephalin, has been iso= lated [305], identified chemically [306], and found to possess antinociceptive activity in mice after ICV injection [307], The interactions of the amines, enkephalin, and the cyclic nucleotides remain to be determined, and the scope for future studies of the mechanisms of action of the opiate analgesics becomes much wider as a result of these more recent studies. 

Rats, which suffer from arthritis have an elevated morphine concentration in their spinal cord and urine. It is presumed, that also the human body produces endogenous morphine for pain regulation during the course of particular illnesses. 

Endorphins endogenous peptides with morphinelike effects (endogenous morphine), the natural ligands for the opiate receptors. See Opioid peptides. 

P450 has also been demonstrated to play important roles in the biosynthesis of endogenous morphine in mammals, catalyzing both (1) the cyclizations of (7 )-reticuline to salutaridine [905] and (2) the elusive 0 -demethylation of thebaine involved in the latter stages of morphine synthesis [906] (Fig. 9.17). With this, a minimal scheme can be proposed with P450 enzymes capable of all oxidative steps in the pathway. 

Interesting recent results indicate that P450 3A5 is more active than P450 3A4 in some reactions. One is the activation of lapatinib [1481]. Another is the 0 -demethylation of thebaine (Fig. 9.17), a critical step in the synthesis of endogenous morphine [906], where P450 3A5 is > 10-fold more active than P450 3A4 [906]. The presence of P450 3A5 in brain (Sect. 7.21.1) may have implications in the relevance of the pathway. 

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