Endogenous Morphine Research Articles

Dark chocolate as a non-pharmacological alternative to reduce dysmenorrhea in adolescents

Dysmenorrhea, menstrual pain often experienced by women of reproductive age, including teenage girls, can cause discomfort and hinder daily activities, necessitating treatment. Chocolate contains copper, which synthesizes neurotransmitters like collagen and endorphins, serving as an analgesic and natural sedative to alleviate pain. This study aimed to assess the effect of dark chocolate on reducing dysmenorrhea in adolescents. This study employed a quasi-experimental research design and was conducted over six months at a polytechnic in Bandung. Pain intensity was measured using a standardized instrument known as the WALIDD score. A total of forty students with primary dysmenorrhea participated in the study, selected through purposive sampling, and were divided into a treatment group and a control group. The independent variables included the administration of dark chocolate, while the dependent variable was the intensity of menstrual pain in students with primary dysmenorrhea. Data were analyzed using an independent t-test. The intervention group, which received education on menstruation and dark chocolate, exhibited a significant reduction in dysmenorrhea pain as early as the second day, with a p-value of <0.001. Administering dark chocolate at a dosage of 35 mg/day from the onset of menstruation helps reduce pain from the first day of menstruation compared to standard therapy, which includes education about menstruation. Chocolate enhances mood due to its copper content, releasing endogenous morphine that inhibits pain impulses. This makes chocolate a non-pharmacological alternative for alleviating dysmenorrhea.

β-Endorphin (an endogenous opioid) inhibits inflammation, oxidative stress and apoptosis via Nrf-2 in asthmatic murine model

Asthma, a chronic respiratory disease is characterized by airway inflammation, remodelling, airflow limitation and hyperresponsiveness. At present, it is considered as an umbrella diagnosis consisting several variable clinical presentations (phenotypes) and distinct pathophysiological mechanisms (endotypes). Recent evidence suggests that oxidative stress participates in airway inflammation and remodelling in chronic asthma. Opioids resembled by group of regulatory peptides have proven to act as an immunomodulator. β-Endorphin a natural and potent endogenous morphine produced in the anterior pituitary gland play role in pain modulation. Therapeutic strategy of many opioids including β-Endorphin as an anti‑inflammatory and antioxidative agent has not been yet explored despite its promising analgesic effects. This is the first study to reveal the role of β-Endorphin in regulating airway inflammation, cellular apoptosis, and oxidative stress via Nrf-2 in an experimental asthmatic model. Asthma was generated in balb/c mice by sensitizing with 1% Toulene Diisocyanate on day 0, 7, 14 and 21 and challenging with 2.5% Toulene Diisocyanate from day 22 to 51 (on every alternate day) through intranasal route. β-Endorphin (5 µg/kg) was administered through the nasal route 1 h prior to sensitization and challenge. The effect of β-Endorphin on pulmonary inflammation and redox status along with parameters of oxidative stress were evaluated. We found that pre-treatment of β-Endorphin significantly reduced inflammatory infiltration in lung tissue and cell counts in bronchoalveolar lavage fluid. Also, pre-treatment of β-Endorphin reduced reactive oxygen species, Myeloperoxidase, Nitric Oxide, Protein and protein carbonylation, Glutathione Reductase, Malondialdehyde, IFN-γ, and TNF-α. Reversely, β-Endorphin significantly increased Superoxide dismutase, Catalase, glutathione, Glutathione-S-Transferase, and activation of NF-E2-related factor 2 (Nrf-2) via Kelch-like ECH-associated protein 1 (Keap1), independent pathway in the lung restoring architectural alveolar and bronchial changes. The present findings reveal the therapeutic potency of β-END in regulating asthma by Keap-1 independent regulation of Nrf-2 activity. The present findings reveal the therapeutic potency of β-Endorphin in regulating asthma.

Beta endorphins - molecules of therapeutics

Endorphins are endogenous morphine, neuropeptides produced in the pituitary gland. There are three types of endorphins beta-endorphins, enkephalins, and dynorphins. Beta-endorphins are an abundant endorphins synthesized and stored in the anterior pituitary gland; it is a precursor of POMC (Proopiomelanocortin). Beta-endorphins has got various mechanisms of actions such as anti-inflammatory activity, analgesic activity, stress buster activity, and immune stimulatory activity can be used to treat various diseases such as chronic inflammatory diseases such as heart disease, Alzheimer’s disease, cancer, auto-immune disease, diabetes mellitus, and aging. This article highlights about the basic research findings of beta-endorphins and mechanisms of actions in management of various diseases.

Alteration in the Expression of Parkinson’s-Related Genes in Rat Hippocampus by Exercise and Morphine Treatments

Parkinson’s disease (PD) as a genetically heterogeneous disease is the second common neurological disorder which is associated with motor deficits and dementia owing to a spreading process of neuronal loss in the brain. Little is known about what affects Parkinson disease, but global efforts are underway to make medicines for treatment of this disease. We suppose, exercise as one of the golden key for overall health and brain-derived neurotrophic factor (BDNF) modulator must have some effects on the degree of PD severity. On the other hand, given the dopamine is one of the indispensable components for the endogenous morphine biosynthesis, a decrease in the level of morphine, may be associated with this disorder. We investigate the rate of true effect of exercise and morphine treatments on the expression of some major heritable genes in PD, including SNCA, LRRK2, Parkin, and DJ-1, by real-time PCR in rat hippocampus. The results indicated that under exercise and morphine treatments, the expression of alpha-synuclein and LRRK2 genes declined, while the expression of Parkin and DJ-1 genes raised. Since this genes expression pattern has been observed in the normal individuals, it can be concluded that exercise and morphine treatments have a positive effect on the improvement of Parkinson disease, and it might act in similar way in humans.

Simultaneous intrathecal injection of muscimol and endomorphin-1 alleviates neuropathic pain in rat model of spinal cord injury.

IntroductionDue to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects. The role of inhibitory GABA system is well proven in reducing neuropathic pain. Also, special attention has been focused on endogenous morphine (endomorphins) in reducing chronic pain originates from damage to the nervous system. The purpose of this study is to investigate the analgesic effect of simultaneous administration of GABA agonist and endomorphin‐1 on neuropathic pain in rat model of spinal cord injury (SCI). The role of oxidative stress, NR1 subunits of NMDA receptors, and α2 subunits of GABA receptors in the spinal cord has also been investigated.MethodsSpinal cord at level of T6–T8 was compressed. Three weeks after spinal cord injury, muscimol and endomorphin‐1 were injected (intrathecally once a day for 7 days) individually or in combination. Mechanical and cold allodynia, thermal and mechanical hyperalgesia were evaluated before injection and 15 and 60 min after injection. At the end of behavioral experiments, histological and biochemical evaluations were done on prepared spinal cord samples.ResultsIsobologram results showed that combination therapy significantly increased the pain threshold comparing to injection of endomorphin‐1 (EM) or muscimol alone. Histological studies indicated the increased expression of α2 subunits of GABA receptors, and NR1 subunits of NMDA receptors in the spinal cord. The combination therapy also increased the glutathione (GSH) and superoxide dismutase (SOD) level and decreased the malondialdehyde (MDA) levels in the spinal cord.ConclusionSimultaneous administration of muscimol and endomorphine‐1 could be a new candidate for alleviation of pain resulting from spinal cord injury.

Odor perception and hedonics in chronic schizophrenia and in first episode psychosis.

Background and purposeThe study evaluated olfactory performance and pleasantness rating of odors in patients with first episode psychosis (FEP) and chronic schizophrenia (SCH) with regard to the severity of psychopathological symptoms and plasma β-endorphin concentration.Patients and methodsTwenty patients with FEP, 27 with SCH and 29 healthy individuals, were recruited to the research . The University of Pennsylvania Smell Identification Test (UPSIT), subjective odor hedonic judgment and plasma levels of β-endorphin (BE) assay were performed in all participants.ResultsIndividuals with SCH revealed higher BE concentration than other study groups (P=0.000). All patients identified pleasant odors poorer than controls, however, SCH made more identification errors (P=0.000) than those with FEP. Moreover, participants with FEP rated pleasant odors as more pleasant than individuals with chronic schizophrenia and healthy controls (P=0.009). Nevertheless, higher β-endorphin level was related with lower scores in pleasant odor identification (Rs=−0.452; P=0.046) and more severe psychotic symptoms in FEP sample. Chronic schizophrenia patients did not demonstrate any relationship between symptom severity, odor identification performance and β-endorphin concentration. No relationship was found between BE concentration and hedonic judgment of the presented odors among all study groups. Chronically ill subjects identified odors significantly more poorly than those with first episode psychosis. Deficits in identifying pleasant odors might not be the only potential risk factor for undergoing chronic, recurrent schizophrenia. All patients subjectively overrated pleasant odors. Those with SCH and more severe negative symptoms made significantly more identification errors.ConclusionThe endogenous morphine system deregulation is observed in first episode psychosis as well as in chronic schizophrenia. In first episode schizophrenia higher beta-endorphin concentration is related to pleasant odor identification deficit.

Endorphins in Anti-Aging Activity - Holistic Approach an Emerging Concept

Endorphins are endogenous morphine, neuropeptide. There are three types of endorphins such as beta-endorphins, enkephalins, dynorphins are produced during stress and pain. Receptors of endorphins are situated on nervous system and immune cells. It has got various activities such as immune stimulatory, anti-inflammatory, and delay aging by reduction of free radicals (ROS, RNS) production by immune cells during oxidative burst.

Endorphins in Anti-Aging Activity - Holistic Approach an Emerging Concept

Endorphins are endogenous morphine, neuropeptide. There are three types of endorphins such as beta-endorphins, enkephalins, dynorphins are produced during stress and pain. Receptors of endorphins are situated on nervous system and immune cells. It has got various activities such as immune stimulatory, anti-inflammatory, and delay aging by reduction of free radicals (ROS, RNS) production by immune cells during oxidative burst.

The association between endogenous opioid function and morphine responsiveness: a moderating role for endocannabinoids.

We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.

Diagnostic value of endogenous morphine in childhood sepsis

To investigate the plasma concentration of endogenous morphine and the value of endogenous morphine in predicting shock, death, and multiple organ dysfunction syndrome (MODS) in children with sepsis. A total of 31 children with sepsis who met the diagnostic criteria were enrolled. According to the presence or absence of shock, they were divided into non-shock group with 19 children and shock group with 12 children. According to the outcome, they were divided into survival group with 22 children and death group with 9 children. According to the presence or absence of MODS, they were divided into non-MODS group with 13 children and MODS group with 18 children. In addition, 16 children with common infection and 31 who underwent physical examination were enrolled as controls. High-performance liquid chromatography-mass spectrometry was used to measure the plasma concentration of endogenous morphine. The receiver operating characteristic (ROC) curve was used to evaluate the value of endogenous morphine in predicting shock, death, and MODS in children with sepsis. No endogenous morphine was detected in the healthy control group. Endogenous morphine was detected in 3 children from the common infection group and in all of 31 children with sepsis. The shock group had a significantly higher plasma concentration of endogenous morphine than the non-shock group (P<0.05). The death group had a significantly higher plasma concentration of endogenous morphine than the survival group (P<0.05). The MODS group had a significantly higher plasma concentration of endogenous morphine than the non-MODS group (P<0.05). The ROC curve showed that endogenous morphine had certain value in predicting shock, death, and MODS in children with sepsis (P<0.05). There is a significant increase in the plasma concentration of endogenous morphine in children with sepsis, and endogenous morphine has a good value in predicting the risk of shock, death, and MODS.

Endorphins – A Novel Holistic Therapeutic Approach to Cancer

Endorphins are endogenous morphine, neuropeptides produced from pituitary gland in response to stress and pain. These are of three types- beta-endorphins, dynorphins, enkephalins, binds to mu, kappa, delta receptors found on immune cells and nervous system. Beta-endorphins is the most abundant endorphin synthesized and stored in the anterior pituitary gland. It has got various activities such as Immune stimulatory activity, anti-inflammatory activity, analgesic activity, stress buster, and anti-aging activity. Immune stimulatory activity by activation of NK cells, macrophages, T-lymphocytes, anti-inflammatory activity by production of cytokines, such as IL-18, 1L-10, analgesic activity by inhibiting substance-p, anti-ageing by suppressing ROS, RNS, free radicals and lengthening telomeres, stress buster activity by decreasing cortisol and nor-adrenaline, dopamine release involved in holistic, preventive, promotive, therapeutic and palliative treatment of cancer without any adverse affects and inexpensive. This article brief about the current concept of novel actions of endorphins in holistic treatment of cancer .

Changes in Melatonin, Cortisol, and Body Temperature, and the Relationship Between Endogenous Melatonin Levels and Analgesia Consumption in Patients Undergoing Bariatric Surgery.

Melatonin has analgesic, anti-inflammatory, sedative, and anxiolytic properties. However, the relationship between endogenous melatonin levels and postoperative analgesic requirements has not been well elucidated in patients undergoing bariatric surgery. We studied endogenous melatonin levels, cortisol levels, body temperatures, and the relationship between the level of endogenous melatonin and postoperative morphine consumption. The trial was conducted among 30 patients who were scheduled for laparoscopic bariatric surgery. Their ages were between 18 and 65years and their BMIs were above 40kg/m2. Secretion of melatonin, cortisol, and body temperature was monitored before the anesthetic induction, at 2h intraoperatively, and at 2, 6, 10, (2:00 A.M.) and 24h postoperatively. For each patient, morphine consumption was assessed at postoperative visits. The primary outcomes were to measure endogenous melatonin levels and to examine the relationship between these levels and morphine consumption. The secondary outcome was to observe the changes in cortisol and body temperature. There was a significant decrease in melatonin levels when preoperative melatonin levels were compared with intraoperative and all postoperative follow-up periods (p< 0.05). When the correlation between plasma melatonin levels and the postoperative morphine consumption of the patients was inspected, there was a significant correlation in all of the follow-up periods (p< 0.05). When preoperative cortisol levels were compared with intraoperative and postoperative cortisol levels, there was a significant difference in the follow-up periods, except two periods (p< 0.05). Body temperatures were similar in all measurement periods. Endogenous melatonin secretion was significantly decreased in the intraoperative and postoperative periods. Furthermore, there was a significant inverse correlation between changes in endogenous melatonin levels and morphine consumption. Clinical Trial Number NCT03107702 from A service of the U.S. National Institutes of Health, clinicaltrials.gov.

The Neuroprotection of Low-Dose Morphine in Cellular and Animal Models of Parkinson's Disease Through Ameliorating Endoplasmic Reticulum (ER) Stress and Activating Autophagy.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Brain endogenous morphine biosynthesis was reported to be impaired in PD patients and exogenous morphine attenuated 6-hydroxydopamine (6-OHDA)-induced cell death in vitro. However, the mechanisms underlying neuroprotection of morphine in PD are still unclear. In the present study, we investigated the neuroprotective effects of low-dose morphine in cellular and animal models of PD and the possible underlying mechanisms. Herein, we found 6-OHDA and rotenone decreased the mRNA expression of key enzymes involved in endogenous morphine biosynthesis in SH-SY5Y cells. Incubation of morphine prevented 6-OHDA-induced apoptosis, restored mitochondrial membrane potential, and inhibited the accumulation of intracellular reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, morphine attenuated the 6-OHDA-induced endoplasmic reticulum (ER) stress possible by activating autophagy in SH-SY5Y cells. Finally, oral application of low-dose morphine significantly improved midbrain tyrosine hydroxylase (TH) expression, decreased apomorphine-evoked rotation and attenuated pain hypersensitivity in a 6-OHDA-induced PD rat model, without the risks associated with morphine addiction. Feeding of low-dose morphine prolonged the lifespan and improved the motor function in several transgenic Drosophila PD models in gender, genotype, and dose-dependent manners. Overall, our results suggest that neuroprotection of low-dose morphine may be mediated by attenuating ER stress and oxidative stress, activating autophagy, and ameliorating mitochondrial function.

Evidence for the presence of morphine like substance and μ opiate receptor expression in Dicrocoelium dendriticum (Trematoda: Dicrocoeliidae)

Parasites for living in host’s body, evade from host’s immune system using variant methods such as production of some molecules with immunosuppressive properties. Of these immunosuppression molecules are morphine and morphine like substances. It can effect on innate and adaptive immunity and also humoral and cellular immunity. The past researches were approved the existence of morphine in the brain and adrenal of beef and in brain of mammalian and also it has been demonstrated as an immune modulator molecule in some invertebrates, some of the nematodes and also a trematode Schistosoma mansoni, But there is no document for morphine evidence in trematode Dicrocoelium dendriticum. Infection with this trematode has much importance either in health of ruminant and economic loos in the meat industry. In addition, this trematode is a zoonosis that there is no proper treatment for it in contrast with the other liver fluke, Fasciola hepatica. We assume that living for a long time in the bile ducts of host is related to morphine like substance as an immune regulatory molecule. We use RP-HPLC method for detection morphine in D. dendriticum and also using reverse transcription polymerase chain reaction (RT-PCR) for μ opioid receptor finding. According to the results D. dendriticum has endogenous morphine like material and also the existence of opioid μ receptor in this trematode was approved. Living in host bile duct for a long time without sever immunopathologycal impact, suggested that probably this worm use of morphine like material as an immunoregulatory molecule and also for escaping from host immune system.

Endorphins–A Novel Hidden Magic Holistic Healer

Endorphins are endogenous morphine, neuropeptide, produced from pituitary gland in response to stress and pain. There are three types of endorphins are beta-endorphins, dynorphins, enkephalins binds to mu, kappa, and delta receptors found on immune cells and nervous system. Beta-endorphins is a most abundant endorphins synthesized and stored in the anterior pituitary gland. It has got various activities such as immune stimulatory, antiinflammatory, analgesic activity, delay aging, stress buster activity involved in preventive, promotive, therapeutic and palliative treatment of various diseases such as cancer, auto-immune diseases, infectious disease without any adverse effects. This article briefs about the novel roles of endorphins especially beta-endorphins and its action in holistic treatment of diseases.

BETA – Endorphins – A Novel Natural Holistic Healer

Endorphins are endogenous morphine synthesized and stored in the anterior pituitary gland in response to pain and stress. There are three types of endorphins such as β-endorphins, dynorphins and enkephalins, has receptors on brain, nervous system and immune cells. Beta-endorphins are abundant endorphins involved in immune-stimulatory activity, stress buster, anti-inflammatory and analgesic activity used for therapeutic, promotive, palliative, preventive, holistic approach of treating diseases such as infectious diseases, cancer, auto-immune diseases. This article briefs about the role of Beta-endorphins and it’s mechanism of actions on various diseases.

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF NEW CODEINE FE(III) COMPLEX

ABSTRACT The reaction of FeCl 3 hexahydrate with C 18 H 20 NO 3 .PO 4 in acetonitrile produced new complex with general formula [Fe(L)]Cl 2 , (L= codeine). Characterization of the ligand and its complex were made by elemental analysis, FT-IR, 1 H-NMR, Raman and UV–visible spectroscopy. This new complex showed antitumor activity against two kinds of cancer cell lines: AGS (Stomach) and MCF-7 (Breast). Cell cytotoxic effects of the ligand and its complex were assayed by MTT and Natural-red tests. The antibacterial activity of ligand and complex against Pseudomonas aeruginosa , Staphylococcus aureus , Streptococcus pyogenes and Escherichia coli were also examined. Keywords: Codeine; Fe(III) complex; Synthesis; Anti-tumor; AGS and MCF-7; Antibacterial. e-mail: mojdeh.golzani@gmail.com INTRODUCTION Natural products play an important role in diseases control and treatment. The plants extracts are used in the treatment of human diseases all the time. From the last century, a scientific interest for phototherapy increased in several medical fields such as immunology, hematology and oncology [1-5].Currently there are three major ways of treating cancer: radiation therapy, surgery and cytotoxic drugs. Application of plants in medicine has affected the identification of natural compounds such as cocaine, morphine, vinblastine, tax land codeine [5-8].Many different coordination compounds and the mechanism of cytotoxic action have been discussed with regard to the development of new antitumor agents [8-15]. Numerous medicinal plants have been screened extensively for their antimicrobial potential worldwide [1, 11]. Morphine and its derivatives have received considerable attention as narcotic and used in lenitive drudge products. Morphine plays an important role in the therapy of acute and chronic pain. Exogenously delivered morphine acts in the body by activating different subtypes of opioid receptors [14].Over the last decades, proposals have accumulated that morphine present in mammalian tissues and fluids comes not only from an exogenous or dietary origin, but may also be biosynthesized de novo. Latest studies have unequivocally proven the existence of a mammalian morphine biosynthetic pathway [15], which consists of at least 19 steps and is different in its primary steps from that occurring in plants [16]. Meanwhile the endogenous morphine biosynthesis takes place in mammals, their cells and tissues are constantly exposed to certain amounts of morphine and its precursors [17].Investigation of lithium effect in opioid receptors on inhibitory avoidance response in mice has been reported. The results suggest that the opioid receptors in the central nervous system may be involved in the retrieval of lithium state dependent learning [18]. The lithium efficacy in controlling behaviors related with dopamine stimulants and manic states has been proposed [19]. Thus, it may be suggested that lithium‘s action may be mediated through dopamine receptors [20].Furthermore interactions between lithium and opioids have been reported. There is evidence that lithium is able to affect some actions of morphine. In particular, it has been shown that lithium inhibits morphine withdrawal signs in morphine-dependent mice [21], reduces the self-stimulation facilitated by morphine and the expression of tolerance to morphine [22] and alters the morphine induced analgesia in mice [23]. Both drugs produce a conditioned taste avoidance response and suppress schedule-induced polydipsia [24]. Another morphine precursor codeine, which stands in the biosynthetic pathway after salutaridinol, had a higher partial agonist efficacy. Their metal chelates are of interest due to their fascinating chemistry as well as antimicrobial and anti-cancer activities. The other natural ligand from plants such as phenolic compound of mono and sesquiterpenoid, flavonoids also can be used in synthesis of metal complex [25].Codeine is generally named codeine phosphate (Cod.P), morphine-3-methyl ether phosphate, methyl-morphine phosphate, or morphine monomethyl ether phosphate. It takes the general formulae of C

Sport physiology, dopamine and nitric oxide – Some speculations and hypothesis generation

Elite Spanish professional soccer players surprisingly showed a preponderance of an allele coding for nitric oxide synthase (NOS) that resulted in lower nitric oxide (NO) compared with Spanish endurance and power athletes and sedentary men.The present paper attempts a speculative explanation. Soccer is an “externally-paced” (EP) sport and team work dependent, requiring “executive function skills”. We accept that time interval estimation skill is, in part, also an executive skill. Dopamine (DA) is prominent among the neurotransmitters with a role in such skills. Polymorphisms affecting dopamine (especially DRD2/ANKK1-Taq1a which leads to lower density of dopamine D2 receptors in the striatum, leading to increased striatal dopamine synthesis) and COMT val 158 met (which prolongs the action of dopamine in the cortex) feature both in the time interval estimation and the executive skills literatures. Our paper may be a pioneering attempt to stimulate empirical efforts to show how genotypes among soccer players may be connected via neurotransmitters to certain cognitive abilities that predict sporting success, perhaps also in some other externally-paced team sports.Graphing DA levels against time interval estimation accuracy and also against certain executive skills reveals an inverted-U relationship. A pathway from DA, via endogenous morphine and mu3 receptors on endothelia, to the generation of NO in tiny quantities has been demonstrated. Exercise up-regulates DA and this pathway. With somewhat excessive exercise, negative feedback from NO down-regulates DA, hypothetically keeping it near the peak of the inverted-U. Other research, not yet done on higher animals or humans, shows NO “fine-tuning” movement. We speculate that Caucasian men, playing soccer recreationally, would exemplify the above pattern and their nitric oxide synthase (NOS) would reflect the norm of their community, whereas professional players of soccer and perhaps other EP sports, with DA boosted by very frequent and intense practice and extra stress from public scrutiny, would potentially have their negative feedback system overwhelmed, were it not that many of them carry the C allele of the NOS3-786T/C polymorphism. Then, even very high DA would not result in so much NO as to shut the system down. We add some evolutionary speculations.

Morphine stimulates nitric oxide release in human mitochondria.

The expression of morphine by plants, invertebrate, and vertebrate cells and organ systems, strongly indicates a high level of evolutionary conservation of morphine and related morphinan alkaloids as required for life. The prototype catecholamine, dopamine, serves as an essential chemical intermediate in morphine biosynthesis, both in plants and animals. We surmise that, before the emergence of specialized plant and animal cells/organ systems, primordial multi-potential cell types required selective mechanisms to limit their responsiveness to environmental cues. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule, were provided with extremely positive evolutionary advantages. Endogenous morphinergic signaling, in concert with NO-coupled signaling systems, has evolved as an autocrine/paracrine regulator of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving morphinergic/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Key to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via endogenous morphine.

Cytochrome P450 3A Enzymes Catalyze the O6-Demethylation of Thebaine, a Key Step in Endogenous Mammalian Morphine Biosynthesis

Morphine, first characterized in opium from the poppy Papaver somniferum, is one of the strongest known analgesics. Endogenous morphine has been identified in several mammalian cells and tissues. The synthetic pathway of morphine in the opium poppy has been elucidated. The presence of common intermediates in plants and mammals suggests that biosynthesis occurs through similar pathways (beginning with the amino acid L-tyrosine), and the pathway has been completely delineated in plants. Some of the enzymes in the mammalian pathway have been identified and characterized. Two of the latter steps in the morphine biosynthesis pathway are demethylation of thebaine at the O(3)- and the O(6)-positions, the latter of which has been difficult to demonstrate. The plant enzymes responsible for both the O(3)-demethylation and the O(6)-demethylation are members of the Fe(II)/α-ketoglutarate-dependent dioxygenase family. Previous studies showed that human cytochrome P450 (P450) 2D6 can catalyze thebaine O(3)-demethylation. We report that demethylation of thebaine at the O(6)-position is selectively catalyzed by human P450s 3A4 and 3A5, with the latter being more efficient, and rat P450 3A2. Our results do not support O(6)-demethylation of thebaine by an Fe(II)/α-ketoglutarate-dependent dioxygenase. In rat brain microsomes, O(6)-demethylation was inhibited by ketoconazole, but not sulfaphenazole, suggesting that P450 3A enzymes are responsible for this activity in the brain. An alternate pathway to morphine, oripavine O(6)-demethylation, was not detected. The major enzymatic steps in mammalian morphine synthesis have now been identified.