Chronic stress can be an extremely detrimental phenomenon because it maintains an artificial state of excitation, whereas acute stress ends this process in a more timely manner.
Therefore, it is not surprising to find proinflammatory phenomena occurring during chronic stress since the system maintains excitability, including that of immune origin.
The cardiovascular system is also subject to the excitatory influence of chronic stress and it maintains an activation state far exceeding the purpose of this response, i.e., oxygen and nutrient delivery to tissues. Regarding the stress response, we surmise that this cellular, tissue and organismic activation is shut off normally by way of cascading chemical messengers designed to terminate the response. Here, based on empirical evidence, we speculate that endogenous morphine via stereoselective opiate receptors (μ3-4) coupled to constitutive nitric oxide release is part of a down regulatory mechanism, assisting in terminating a stress response if appropriate. Indeed, the enzymes capable of synthesizing morphine are subject to variations, which may, in part, account for the detrimental effects of chronic stress since the process cannot now be terminated easily given that the morphinergic signaling may be subject to insufficiency. Taken together, this speculative review attempts to provide novel answers to an old problem.
Proinflammation is a widespread phenomenon as is stress. Proinflammation is potentially associated with the stress pathophysiology and therefore may be connected with various stress-related, as well as stress-unrelated diseases , [2,3]. Moreover, proinflammation possesses a close correlation , e.g., with type 1 immune response pathways , [4,5]. Stress also modifies these immune response pathways, e.g., type 1 and type 2 modulation . Hence, proinflammation can be identified as a common denominator in various disease states and as a ‘common ground’ of distinct pathological states, yet interconnected on the molecular level [2-4]. However, the association of proinflammation with stress and cardiovascular disease processes has only recently emerged in the scientific focus.
Like stress, proinflammation seems to represent a crucial autoregulatory concept. This is not astonishing since proinflammation normally serves a positive biological goal. Proinflammatory activities, for example, are initiated to overcome infection or invasion of potentially deleterious biological agents (bacteria, viruses, parasites etc.). Moreover, while fighting invasion, proinflammation – if successfully implemented – usually shortens biological ''battles'' and therefore ameliorates disease-related or subjectively unpleasing phenomena. However, proinflammation has to be stopped and terminated in time, that is, (auto)regulated and controlled. This can become a problem due to the actual invader or biological threat that is encountered, or to a possible deterioration of the underlying self-control mechanisms. Thus, proinflammation can serve in both beneficial and deteriorating capacities . The specific outcome that emerges is critically linked, e.g., to the state of the immune or cardiovascular system and its molecular and stress-related processes that emerge under pressure or perturbation [1-3]. Stress autoregulation and the molecular processes that build this capacity, therefore, have now moved into the scope of the biological and medical sciences.
Stress is a natural, biological and, at times, useful phenomenon. Stress describes the effects of psychosocial and environmental factors on physical and/or mental well-being [1,6,7]. Stress implies a challenge that requires behavioral, psychological, and physiological changes (adaptations) to be successfully met, therefore using a state of hyperarousal for the initiation of necessary counteracting reactions [1,6-9]. This state of hyperarousal involves physiological mechanisms that are known as the stress or ‘fight-or-flight’ response, a set of physiological changes that occur in stressful situations and that prepare the stressed organism either to fight or to flee. This state of alertness was first described by Walter Cannon almost a century ago [10-12]. Years later, Hans Selye, among others, refined the physiological stress concept and its significance for biology and survival [6,7]. Modern concepts and recent studies have eventually associated the stress theory with human ailments and its neurobiological implications [8,9,13-18].
Stress occurs when we meet a sudden challenge and are forced to act/react in order to survive or to endure. When a zebra unexpectedly meets a lion, its physiology turns towards alarm, i.e., fight or flight, or eventually ‘freeze’, when the challenge is simply overwhelming implying a physiological black out [13,15,16]. Every bodily or mental activity is now scanned for the usefulness or deleteriousness in responding to the challenge, the stressor. Beneficial mechanisms will be enforced other mechanisms will be shut-down. This is natural and, at times, helpful, although there are exceptions. Following a successful escape or fight, the body naturally recovers and the mind relaxes. Autoregulatory messengers and signaling molecules effortlessly enable this rebound or recreational state . However, problems may occur when stress endures for too long, is too massive or the physiology not suitably fitted to fight a particular stressor, or when enough time for recovery is not allowed [1-6,9,13,19-21]. In addition, at the organismic level, the biochemical response machinery responsible for turning off a stress reaction may be damaged. This seems to be a real human dilemma equipped with the very same stress response mechanisms that the zebra fortunately possesses, we usually don’t have to oppose life-threats in forms of lions or other external enemies in our daily life [15,16,20,22]. Thus, we start to think about the stresses and dangers in the future, the stressors and potentially stressful situations that might come, or the things that we encountered in the past, regarded as stressful . Furthermore, we may start to dwell about our potentially suboptimal coping and resistance capacities in the present, thereby diminishing these very same capacities, causing us self-inflicted stress and impairment of our defense, i.e., ‘cognitive constipation’ . This useful and helpful mechanism that was designed to help us cope with stressors may become deleterious, and stress-related diseases consequently emerge [4,17,23]. This is the critical path that underlies much of modern stress and human stress-related diseases. However, we not only possess the endogenous capacity to self-inflict stress and harm, i.e., self-harm, but also to self-manage it, reduce its impact, be self-efficacious and endogenously heal or prevent stress disorders via stress management .
Proinflammation, stress and diseases
Proinflammation is a phenomenon that is involved in many stress-related diseases [1,4]. Stress is important because it represents a common feature of life  and it may further trigger the activation of biological immune response pathways, including the proinflammatory type 1 response . However, stress, especially ''adequate'' amounts of acute stress (in contrast to ''overwhelming'' or chronic stress), usually favors and facilitates type 2 immune response pathways (humoral response) [1,4,24-26].
Proinflammation is a common (patho)physiological state, one that may either exert beneficial (when utilized as an adequate defense mechanism) or detrimental effects (particularly in the long-term, when proinflammation endures) . Numerous cytokines are present within proinflammatory foci. Interleukin (IL)-1 and tumor necrosis factor (TNF) are of particular importance. IL-1 and TNF-alpha play a major role in coordinating mechanisms which command (pro)inflammation [27,28]. Upon their action, many different cells produce lipidic mediators, proteolytic enzymes and free radicals, all directly responsible for the noxious effects detectable and eventually leading to thorough disease processes . IL-1 and TNF exert cytotoxic effects on vascular endothelium, cartilage, bone, muscle, and other tissues . In contrast, soluble TNF receptors, released during inflammation, are the direct inhibitors of TNF. Glucocorticoids, released following a cascade of events initiated by IL-1, TNF-alpha and IL-6, involving the neuroendocrine axis (i.e., stress), also inhibit proinflammatory cytokine productions [2,28]. Thus, feedback mechanisms exist that are set up to keep proinflammation in balance. However, once the proinflammatory pathway gets activated and a prolonged or strong stimulation endangers homeostasis, deteriorating pathophysiological developments may occur. These may manifest themselves in different regions of the body. Thus, different diseases with a common (overlapping) pathophysiological background and similar patterns of cytokine activity may develop.
Recent studies suggest that (pro)inflammation plays a role in the pathogenesis of cardiovascular diseases. Not only in atherosclerosis and coronary artery disease  but also in other diseases of the circulatory system, proinflammation may be involved [23,29]. For example, IL-1, TNF-alpha, and mainly IL-6 are the three most important known proinflammatory cytokines involved in the pathogenesis of hemodialysis-related and cardiovascular diseases . Nitric oxide (NO) pathways may further play a role. Also, an elevated blood pressure (i.e., arterial hypertension) may induce an inflammatory state in the arterial wall through both immune response and mechanical signaling pathways . The generation of reactive oxygen species and subsequent up-regulation of redox-sensitive proinflammatory gene products are common endpoints of these pathways [4,23,30].
Atherosclerosis is characterized by a non-specific local inflammatory process which is accompanied by a systemic response [31-33]. A number of prospective studies in initially healthy subjects and in patients with known atherosclerosis have convincingly demonstrated a strong and independent association between even slightly elevated concentrations of various systemic biomarkers of inflammation and a number of cardiovascular events [34,35]. Indeed, the observation that almost half of all myocardial infarctions and strokes occur in persons without elevated levels of low-density lipoprotein (LDL) cholesterol, one of the classical risk factors for cardiovascular diseases, has prompted the search for factors or markers other than hyperlipidemia that contribute to the development or point towards the existence of atherosclerosis. Evidence indicates that inflammation plays a substantial role in plaque progression and rupture. For instance, C-reactive protein (CRP), the classical acute phase protein, seems to be the marker of choice in this clinical situation [33,36-38]. Moreover, combining LDL and CRP measurements may further increase the explanatory power of related test procedures, i.e., better prognostic information [32,35]. This may be due to the fact that CRP and LDL cholesterol measurements tend to identify different high-risk groups . However, CRP is a stronger predictor of cardiovascular events than the LDL cholesterol level . In addition, recent research has suggested that CRP may not only be a risk factor, but may be directly involved in the pathogenesis of atherosclerosis . This suggestion still has to be investigated further. However, statins have been shown to reduce levels of CRP through mechanisms independent of their effects on lipid levels . Initial clinical studies also suggest that CRP levels may have utility in the targeting of statin therapy, particularly in primary prevention . These results still need direct and thorough testing to determine whether statin therapy will benefit persons without overt hyperlipidemia but with evidence of systemic inflammation. Also, indications exist that other drugs with positive effects on cardiovascular outcome, e.g., antidiabetic medications, may have antiinflammatory capacities in addition to their actual properties as well. A new ''wave of research'' in the field of inflammation/antiinflammation has thus recently been initialized. Taken together, proinflammatory activity may be regarded as a marker or even risk factor (contributor) of atherosclerosis and may predict severe or fatal myocardial/vascular events . Proinflammation may go along with a number of negative cardiovascular developments, like atherosclerosis, plaque formation and rupture, endothelial dysfunction, etc. . Moreover, certain treatments that reduce coronary risk, e.g. lipid lowering drugs or even stress management strategies (lifestyle modification programs etc.) [40,41], may also limit inflammation . In the case of lipid lowering, the ''innate'' antiinflammatory effect does not appear to correlate with reduction in LDL levels alone . These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this condition of growing worldwide importance .
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine and/or colon of unknown etiology in which patients suffer from severe diarrhea, rectal bleeding, abdominal pain, fever, and weight loss [42,43]. Active episodes of IBD are characterized by vasodilatation, venocongestion, edema, infiltration of large numbers of inflammatory cells, and erosions or ulcerations of the bowel [2,42,43].
It is becoming increasingly apparent that chronic gut inflammation (i.e., IBD) may result from a dysregulated, imbalanced, immune response as evidenced by a sustained overproduction of proinflammatory cytokines and mediators . Many of these T helper (Th)1 and macrophage-derived cytokines and lipid metabolites are known to activate microvascular endothelial cells, thereby promoting leukocyte recruitment into the intestinal interstitium and inflammation . Normally the balance between Th1 and Th2 pathways can be maintained and it is not clear why in IBD this balance is so much endangered (i.e., the susceptibility to proinflammation is enhanced). It is possible a breakdown in protective antiinflammatory components of the immune response initiates chronic gut inflammation [42,44].
The normal intestinal immune system is under a balance in which proinflammatory and antiinflammatory cells and molecules are carefully regulated to promote a normal host mucosal defense capability without destruction of intestinal tissue [4,45]. Once this careful regulatory balance is disturbed, nonspecific stimulation and activation can lead to increased amounts of potentially destructive (pro)inflammatory molecules [2,45]. The concept of balance/homeostasis and regulation of normal mucosal immune and inflammatory events is indicative of how close the intestine is to developing severe inflammation .
The intestinal mucosal immune system is constantly stimulated by lumenal contents and bacteria . Highly stimulatory bacterial cell wall products, for example, are capable of activating macrophages and T lymphocytes to release potent proinflammatory cytokines, including IL-1, -6, and TNF-alpha . Hence, these cytokines increase the presence of human leukocyte antigen (HLA) class II antigen-presenting molecules on the surfaces of epithelial cells, endothelial cells, macrophages, and B cells, thus increasing their ability to present lumenal antigens and bacterial products [2,4,45]. The proinflammatory cytokines IL-1 and TNF-alpha also increase the ability of epithelial cells, endothelial cells, macrophages, and fibroblasts to secrete potent chemotactic cytokines, such as IL-8 and monocyte chemoattractant protein 1 (MCP-1), which serve to enhance the movement of macrophages and granulocytes from the circulation into the inflamed mucosa [2,45]. Thus, through lumenal exposure to nonspecific stimulatory bacterial products, the state of activation of the intestinal immune system and mucosal inflammatory pathways become markedly up-regulated . This raises the question of whether there is a deficiency in effective down-regulation through the absence of normally suppressive cytokines such as IL-4, -10, transforming growth factor-beta (TGF-beta), and IL-1 receptor antagonist [4,24,45]. Normally, the turning off of the active and potentially destructive inflammatory events should occur following the resolution of a bacterial or viral infection that has been appropriately defended against and controlled by the mucosal immune system . In IBD, however, the down-regulatory processes that should turn off the inflammatory - intentionally protective - pathways, once the pathogenic agent has been cleared, appear to be deficient or only partially effective [2,45]. Clearly, a high degree of stress-sensitivity may play a significant role here. Again, proinflammation itself represents a reasonable - and most often effective - biological defense mechanism that yet has the capability of becoming detrimental when it cannot be controlled appropriately.
Studies that have investigated IBD have improved our molecular understanding of the pathophysiology of ulcerative colitis and Crohn''s disease . Several proinflammatory and immune-regulatory cytokines are up-regulated in the mucosa of patients with IBD, and similarities in the cytokine profiles of ulcerative colitis and Crohn''s disease have been elucidated . TNF-alpha has been shown to represent a crucial component of the chronic mucosal inflammation that is pathognomonic in IBD and seems to be particularly of importance in the pathogenesis of Crohn''s disease [2,46]. Additionally, substantial concentrations of inducible nitric oxide synthase (iNOS), IL-1, TNF-alpha, and INF-gamma have been detected in inflammatory epithelial cells (inflammatory infiltrate) of ulcerative colitis/Crohn''s disease patients, whereas IL-6 activity seems to be significantly enhanced in the adrenal glands of these patients [47-50]. Thus, (chronic) proinflammation apparently is a fundamental component of IBD.
In infectious and parasitic diseases proinflammatory activities, by nature, are detectable. The defense of microbiological invaders is one of the most urgent and important tasks of proinflammatory immune response pathways. However, proinflammation, and particularly when enduring, chronic, or uncontrolled is also responsible for many negative or detrimental concomitant phenomena and disease processes that accompany the defense of infectious agents. Yet, these ''side effects'' of proinflammation itself can become a threat and may even meet the criteria for disease promoting factors (see above). Therefore, we find proinflammatory activity as a common denominator or background underlying devastating pathophysiological mechanisms in various infectious diseases. In this regard, various parasites also attempt to down-regulate the host proinflammatory response to ensure their survival [2,51-53].
Autoimmune diseases have a close association with proinflammatory pathways. In (autoimmune) glomerulonephritis, for example, iNOS activity, TNF-alpha and interferon (IFN)-gamma production have been observed . Rheumatoid arthritis (RA) regularly shows proinflammatory activity. Protective and detrimental NO effects have been observed in RA (iNOS/cNOS activity) [55-58]. Additionally, NF-kappaB activation, proinflammatory cytokine production (IL-1, IL-6, IL-8, TNF-alpha, GM-CSF), hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and an involvement of the sympathetic nervous system (SNS) have been proven [1,2,4,58-60]. Again, stress may be fundamentally involved in proinflammatory pathophysiological developments of importance in RA [2,61]. Here, the crucial step seems to be represented by a chronic synovial inflammation that is related to a state of prolonged proinflammation [2,4,58-61].
In diabetes mellitus type 1, the destruction of the pancreatic islet cells via proinflammatory pathways seems to represent an initial critical step of disease onset/development [62,63]. Also, deleterious proinflammatory NO (iNOS) activity and cytokine production has been detected in pancreatic islet cells/pancreatic islet destructive macrophages of diabetic mammals [64-66]. In addition, proinflammatory IL-6 and TNF-alpha production may promote vascular adhesion  and TNF-alpha has been shown to be associated with dyslipidaemia and increased blood pressure adding to an already enhanced vascular disease risk related to type 1 diabetes mellitus . Metabolic syndrome, being overweight, and diabetes mellitus type 2 are associated with (pro)inflammation and elevated serum CRP concentrations as well [2,33]. This correlation strongly supports the hypothesis that atherosclerosis or other cardiovascular diseases (see above) and type 2 diabetes share a common underlying pathophysiology .
Recently, we have discussed the significance of immune processes in Alzheimer’s and Parkinson’s disease [68,69]. Indeed, proinflammation-related free radical generation, either contributing to or associated with enhanced immune responsiveness, may be regarded as an initiating factor here [3,68,69]. Hence, neuronal degeneration as detectable, for instance, in Alzheimer’s disease (AD) may be associated with inflammatory processes and these may further be connected with the stress pathophysiology. Proinflammatory elevated IL-6 concentrations have been verified in the brains of AD patients . Thus, IL-6 expression may precede neuronal changes in AD . Moreover, several studies indicate that IL-6 expression is related, for example, to psychosocial stress, and therefore, chronic stress and (pro)inflammation may significantly contribute to the pathophysiology underlying AD and dementia . Taken together, proinflammation apparently is involved in many different pathophysiological disease processes. Moreover, proinflammatory (pre)conditions may serve as an important and common pattern in various diseases.
Immune processes, stress regulation and endogenous morphine
Recently, it was demonstrated that human white blood cells (WBC) and invertebrate ganglia contain and have the ability to synthesize morphine and release it into the microenvironment [71,72]. Additionally, human stem cells were found to contain an opiate subtype receptor mu-3 like or mu-4, which only responds to morphine and is coupled to constitutive NO release as previously described for mu-3 [73,74]. Human vascular endothelial cells contain morphine and have the mu3-NO coupled opiate receptor [73,75]. These studies support earlier studies demonstrating a presence of endogenous morphine and morphine 6 glucuronide in animal tissues, including adrenal [76-86]. Taken together, these studies provide empirical evidence that the synthesis of morphine by various tissues and diverse animals is more widespread than previously thought.
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 [72,87,88]. Furthermore, cholinergic nicotinic processes have also been shown to be involved with endogenous morphine processes via novel nicotinic receptors, which can modulate cellular morphine release [89-94]. These results also strongly suggest that these neurotransmitter/neuroimmune chemical messengers exhibit relationships indicative of autocrine and paracrine signaling . Endogenous morphine is synthesized via established and predictable components of the catecholamine pathway [71,72]. Its synthesis and release results in NO release via diverse tissue sources, which serves as a negative feedback modulator, effecting key enzymes in the pathway, such as catechol-O-methyltransferase (COMT), tyrosine hydroxylase (TH) and CYP2D6 [81,84,89,90,92-106]. Interestingly, early on a relationship was found with dopamine, a morphine precursor, and serotonin [107-109]. It appears that gene expression microarray has captured these relationships, which have been validated over the years in diverse animals and tissues.
As is the case for catecholamines, morphine-nitric oxide coupling also appears to be part of stress modulation, i.e., down regulating the stress response [110-114]. Interestingly, endogenous morphine release is enhanced following surgical, environmental, thermal and psychological stressors [79,115-122], suggesting its presence is required to partially mediate the stress response. In this regard, endogenous morphine levels increase post-stress as compared to pre-stress, suggesting a role in terminating the stress response [123-126]. The enzyme phenylethanolamine N-methyltransferase (PNMT) has been suggested to participate in the biosynthesis of morphine . PNMT’s most well studied function is the production of the terminal catecholamine, epinephrine. PNMT is present in high concentrations in the adrenal medulla, but it can also be found in nervous and cardiac tissues . Tissues of the adrenal medulla as well as sympathetic nerves are both derived during development from neural crest cells . PNMT mRNA expression can be up regulated by stress hormones . Similarly, morphine levels are increased by exposure to stress hormones , again suggesting that endogenous morphine becomes active post-stress to restore homeostasis. The presence of morphine in an adrenal chromaffin cell line  and in rat adrenal glands  as well as the secretion of morphine-6-glucuronide by adrenal chromaffin cells  suggests the involvement of PNMT, and other enzymes found in the adrenal glands, in morphinergic processes.
Morphine and epinephrine levels can be increased by stress hormones [129,130,133] placing these chemical messengers in an important survival pathway. In rats without pituitary glands, glucocorticoids and dexamethasone stimulated PNMT mRNA production . Conversely, decreased corticosteroids have been linked to decreased PNMT activity . In adrenal glands, glucocorticoids are needed for PNMT expression . Corticotropin releasing hormone knockout mice do not up regulate their PNMT mRNA in response to stress . The presence of normal glucocorticoid signaling may be necessary for a functional morphine biosynthetic system. If PNMT is serving to synthesize morphine as well as epinephrine, there might be multiple forms of this enzyme to perform these actions. Different forms of PNMT mRNA exist in adrenal glands and in cardiac tissue . The heart contains two forms, one containing introns and the other is an intronless message. The adrenal gland only contains the intronless form [127,137]. The intronless form’s expression is increased by dexamethasone and the intron containing form is decreased . In the heart, the intronless message can increase blood pressure, glucose and lymphocyte cytokine production . The PNMT responsible for morphine synthesis has yet to be characterized.
The understanding that chronic stress can enhance and maintain a proinflammatory state links these phenomena. Furthermore, since cardiovascular disorders can also be part of the same stress circuitry and exhibit proinflammatory characteristics, this makes the phenomenon of proinflammation central in our hypothesis. Newer information provides empirical evidence for a major down-regulatory role of endogenous morphine and morphine-nitric oxide coupling in the processes just described, i.e., stress regulation, proinflammation, etc. Given the dependency of morphine signaling on catecholamine presence raises the issue of morphine insufficiency . In other words, when the brake is missing this uncontrolled level of excitation may attribute to catecholamine activation in stress, in many tissues, and contribute to the pathologies that they manifest, e.g., (un)controlling blood pressure. This appears to be true since gene variations occur in both the catecholamine and morphine synthesis pathways, making some forms of the critical enzymes more efficacious. The introduction of morphinergic signaling as a critical component of stress termination on the tissue and organismic level is a novel hypothesis that has been supported by past empirical data and awaits future studies for further validation.
Nonstandard Abbreviations: CRP, C-Reactive Protein; HPA, Hypothalamic-Pituitary-Adrenal axis; IBD, Inflammatory Bowel Disease; IFN, Interferon; IL, Interleukin; iNOS, Inducible Nitric Oxide Synthase; RA, Rheumatoid Arthritis; Th, T Helper Cell; SNS, Sympathetic Nervous System; TNF, Tumor Necrosis Factor
T Esch - Neuroscience Research Institute, State University of New York, College at Old Westbury, NY 11568, USA; Division of Integrative Health Promotion, Coburg University of Applied Sciences, Coburg, Germany
KJ Mantione - Neuroscience Research Institute, State University of New York, College at Old Westbury, NY 11568, USA
GB Stefano - Neuroscience Research Institute, State University of New York, College at Old Westbury, NY 11568, USA
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