The gluten syndrome: A neurological disease

juni 25, 2013 av Marius

Nevner det meste om gluten relatert til nerveproblemer. Noe av årsaken ligger i at det blir en autoimmun plage med antistoffer i nerver, som etter hvert gir nerveskader. 64% av de med cøliaki har også nevropati.

http://integrativehealthconnection.com/wp-content/uploads/2011/11/The-gluten-syndrome-A-neurological-disease-21.pdf

Hypothesis: Gluten causes symptoms, in both celiac disease and non-celiac gluten-sensitivity, by its adverse actions on the nervous system.
Many celiac patients experience neurological symptoms, frequently associated with malfunction of the autonomic nervous system. These neurological symptoms can present in celiac patients who are well nourished. The crucial point, however, is that gluten-sensitivity can also be associated with neurological symptoms in patients who do not have any mucosal gut damage (that is, without celiac disease).
Gluten can cause neurological harm through a combination of cross reacting antibodies, immune com- plex disease and direct toxicity. These nervous system affects include: dysregulation of the autonomic nervous system, cerebella ataxia, hypotonia, developmental delay, learning disorders, depression, migraine, and headache.
If gluten is the putative harmful agent, then there is no requirement to invoke gut damage and nutri- tional deficiency to explain the myriad of the symptoms experienced by sufferers of celiac disease and gluten-sensitivity. This is called ‘‘The Gluten Syndrome”.

A mechanism for such nerve damage might be through autoimmune damage [15]. A number of nerve and brain antibodies have been detected. Anti-ganglioside antibodies have been detected in 64% of patients with celiac disease who had also been troubled with some sort of neuropathy [16]. These auto-antibodies have been shown to bind to a number of critical nerve sites that will go on to damage the nerve.

Intermittent Hypoxia Research in the Former Soviet Union and the Commonwealth of Independent States: History and Review of the Concept and Selected Applications

juni 23, 2013 av Marius

Svært viktig review om IHT – intermittend hypoxia training – som det har blitt gjort mye forskning på i russland, men først nå begynt å bli interessant i vesten. Nevner hvordan co2 reageer på hypoxi, og nervesystemet og vevet og i mitchondria, inklidert at SOD øker med 70% og at IHT normaliserer NO som lagres i blodkarene. Om at IHT kan brukes i behandling av sykdommer, inkludert strålingskader fra Chernobyl. Metoden er en «rebreathing» frem til O2% er nede på 7% – ca. 5 minutter daglig i 3 dager.

http://altitudenow.com/images/Hypoxia_in_USSR.pdf

To the present day, intermittent hypoxic training (IHT) has been used extensively for altitude preacclimatization; for the treatment of a variety of clinical disorders, including chronic lung diseases, bronchial asthma, hypertension, diabetes mellitus, Parkinson’s disease, emotional disorders, and radiation toxicity, in prophylaxis of certain occupational diseases; and in sports.

The basic mechanisms underlying the beneficial effects of IHT are mainly in three areas: regulation of respiration, free-radical production, and mitochondrial respiration. It was found that IHT induces increased ventilatory sensitivity to hypoxia, as well as other hypoxia-related physiological changes, such as increased hematopoiesis, alveolar ventilation and lung diffusion capacity, and alterations in the autonomic nervous system.

Due to IHT, antioxidant defense mechanisms are stimulated, cellular membranes become more stable, Ca2+ elimination from the cytoplasm is increased, and 02 transport in tissues is improved. IHT induces changes within mitochondria, involving NAD-dependent metabolism, that increase the efficiency of oxygen utilization in ATP production. These effects are mediated partly by NO-dependent reactions.

Particularly at issue are the effects in humans of such transient bouts of hypoxia when repeated many times, a practice designated as intermittent hypoxia. Furthermore, when intermittent hypoxia as a specific protocol is employed to accomplish a particular aim, for example, acclimatization to high altitude, we use the term intermittent hypoxic training or IHT.

The interested reader is referred to more extensive recent scientific and historical reviews and investigative reports in Russian and Ukrainian, particularly as related to the potential thera- peutic effects of intermittent hypoxia (Berezovsky et al., 1985; Karash et al., 1988; Meerson et al., 1989; Anokhin et al., 1992; Berezovskii and Levashov, 1992; Donenko, 1992; Ehrenburg, 1992; Fesenko and Lisyana, 1992; Vinnitskaya et al., 1992; Serebrovskaya et al., 1998a,b; Volobuev, 1998; Chizhov and Bludov, 2000; Ragozin et al., 2000). Noted also is the use of IHT in the prophylaxis of professional occupational diseases (Berezovsky et al., 1985; Karash et al., 1988; Serebrovskaia et al., 1996) and in sports (Volkov et al., 1992; Radzievskii, 1997; Kolchinskaya et al., 1998, 1999). Recent reviews from Western Europe and North America are also given (Bavis et al., 2001; Clanton and Klawitter, 2001; Fletcher, 2001; Cozal and Cozal, 2001; Mitchell et al., 2001; Neubauer, 2001; Prabhakar, 2001; Prabhakar et al., 2001; Wilber, 2001).

During successive altitude exposures, compared with the initial exposure, the higher ventilation and blood arterial oxygen saturation, together with the lower blood Pco2, implied that ventilatory sensitivity to hypoxia had been increased.

In the intervening years to the present, intermittent hypoxia has been used extensively in the Soviet Union and the CIS not only for altitude pre acclimatization (Gorbachenkov et al., 1994), but also it has been proposed for treatment of a variety of clinical disorders, including chronic lung diseases and bronchial asthma in children and adults (Meerson et al., 1989; Anokhin et al., 1992; Berezovskii and Levashov, 1992; Donenko, 1992; Ehrenburg and Kordykinskaya, 1992; Fesenko and Lisyana, 1992; Redzhebova and Chizhov, 1992; Vinnitskaya et al., 1992; Lysenko et al., 1998; Serebrovskaya et al., 1998b; Chizhov and Bludov,2000; Ragozin et al.,2000, 2001), hypertension (Meerson et al., 1989; Potievskaya and Chizhov, 1992; Rezapov, 1992), emotional disorders (Gurevich et al., 1941), diabetes mellitus (Kolesnyk et al., 1999; Zakusilo et al., 2001), Parkinson’s disease (Kolesnikova and Serebrovskaya, 1998; Serebrovskaya et al., 1998a), inflammatory processes (Tkatchouk, 1994; Tsvetkova and Tkatchouk, 1999), radiation toxicity (Karash et al., 1988; Sutkovyi et al., 1995; Serebrovskaia et al., 1996; Strelkov, 1997; Strelkov and Chizhov, 1998), and certain occupational diseases (Berezovsky et al., 1985; Karash et al., 1988; Rushkevich and Lepko, 2001).

If so, then in normal humans only a few minutes of daily hypoxic exposure rapidly induces detectable increments in hypoxic ventilatory response, a hallmark of altitude acclimatization.

Hypocapnia occurs with altitude acclimatization and ventilation remains increased for days after the subjects return to sea level. By contrast, in the two above studies, eucapnia was maintained during the hypoxic exposures and neither normoxic venilation nor normoxic PC02 was altered by IHT, suggesting that only the hypoxemia and not changes in PC02 (or pH) were involved.

Changing CO2, either for the carotid body or the brain, did not induce ventilatory acclimatization to hypoxia. The work from Bisgard’s laboratory suggested that ventilatory acclimatization to hypoxia in the goat depends almost exclusively on the carotid body’s response to low oxygen. If similar mechanisms operate in humans, then ventilatory acclimatization to hypoxia, operating via the carotid body and independent of changes in pH or PCO2, can be induced by IHT. What is remarkable is that such brief periods of hypoxia can have such clearly measurable increases in the ventilatory response to hypoxia.

In addition to increasing hypoxic ventilatory sensitivity, CIS investigators have reported that IHT increases tidal volume and alveolar blood flow during exercise, improves matching of ventilation to perfusion, increases lung diffusion capacity, redistributes peripheral blood flow during exercise, decreases heart rate, increases stroke volume, and increases blood erythrocyte counts (Volkov et al., 1992; Kolchinskaya, 1993; Radzievskii 1997; Kolchinskaya et al., 1999; Maluta and Levashov, 2001). These effects have been considered to be beneficial in training athletes (Volkov et al., 1992; Radzievskii, 1997). Such findings await independent confirmation from others.

The spectral analysis suggested that after IHT there was greater parasympathetic preponderance during the hypoxic challenge than in the control group. These novel studies conducted in Ukraine suggested that IHT mimicked the usual acclimatization to high altitude, with its primarily greater parasympathetic activity (Reeves, 1993; Hughson et al., 1994). Such activation of the parasympathetic system by IHT was supported by experiments in rats (Doliba et al., 1993; Kurhalyuk et al., 2001a, b, see below).

Among these effects are that brief hypoxic stimuli of only several minutes per day for only a few days give responses that last many days, even weeks, and also that IHT apparently affects a multitude of normal functions and disease states.

This work, as well as more recent studies (Lukyanova, 1997; Sazontova et al., 1997; Kondrashova et al., 1997; Temnov et al., 1997; Lebkova et al., 1999), indicated that the basic molecular response to any type of hypoxic challenge involves the mitochondrial enzyme complexes (MchEC). There is evidence that energy metabolism under acute hypoxia is affected even before a significant decrease in oxygen consumption becomes measurable and before cytochrome c oxidase (CO) activity is significantly reduced.

In the cascade of hypoxia-induced metabolic alterations, MchEC I is most sensitive to intracellular oxygen shortage. The reversible inhibition of MchEC I leads to both the suppression of reduced equivalent flux through the NAD-dependent site of the respiratory chain and the emergency activation of compensatory metabolic pathways, primarily the succinate oxidase pathway. The switch of energy metabolism to this pathway is the most efficient energy-producing pathway available in response to a lack of O2 (Lukyanova et al., 1982).

Skulachev (1996) proposed a two-stage mechanism that allows mitochondria to regulate O2 concentrations and to protect against oxidative stress: (1) «soft» decoupling of oxidative phosphorylation for «fine-tuning» and (2) decrease of the reduction level of respiratory chain components by opening nonspecific mitochondrial inner membrane pores as a mechanism to cope with massive O2 excess.

However, parallel nonenzymatic processes result in O2 formation. This is especially the case when 02 concentrations reach the capacity of the respiratory chain enzymes. Reduction in O2 concentrations leads to an exponential decrease in radical formation. Skulachev (1995) hypothesizes that mitochondria have a mechanism for «soft» decoupling in stage 4 of the respiratory chain. This mechanism prevents the complete inhibition of respiration, the complete reduction of respiratory carriers, and the accumulation of reactive compounds such as ubisemiquinone (CoQ·-). Such a mechanism will be activated, for example, if the capacity of the respiratory chain is decreased due to a reduced availability of ADP.

In contrast to the constriction of capillaries, which prevents undesirably high O2 concentrations in tissue, «soft» decoupling allows fine-regulation on an intracellular level.

Adaptation to hypoxia by an intermittent hypoxic challenge is associated with the expression of, and a shift toward, enzyme isoforms that can efficiently function in a mitochondrial environment with high concentrations of reduced equivalents as generated during hypoxia. This prevents inactivation of the MchEC and may constitute one of the adaptation mechanisms triggered by intermittent hypoxia.

One of the most significant peculiarities of adaptation to intermittent hypoxia is free-radical processes.

The periods of reoxygenation could lead to oxygen radical formation, which might be analogous to that occurring with normoxic reperfusion of transiently hypoxic or ischemic tissues (Belykh et al., 1992; Meerson et al., 1992a). If periods of hypoxia followed by normoxia led to formation of oxygen radicals, but if the hypoxia were much briefer than the periods of normoxia, and if the exposure sequence were repeated over days, then one might expect that antioxidant defenses could be enhanced much more effectively than in sustained hypoxia.

In a recent study rats were given shorter hypoxic exposures: 15 min five times daily for 14 d (Kurhalyuk and Serebrovskaya, 2001). When they were subsequently challenged by exposure to 7% oxygen, blood catalase and glutathione reductase activity were increased and malon dialdehyde concentration was half that of non-IHT controls. The findings were consistent with the concept that intermittent hypoxia stimulates increased antioxidant defenses.

While there was considerable individual variability in the findings (Table 2), our indexes of oxidant stress before IHT were higher in the Chernobyl workers. We used a program of IHT: isocapnic, progressive, hypoxic rebreathing lasting for 5 to 6 min until inspired air O2 reached 8% to 7%, with three sessions, separated by 5 min, of normoxia, per day for 14 consecutive days. The use of IHT was accompanied by a decrease of spontaneous and hydrogen peroxide-initiated blood chemiluminescene, as well as considerable reduction of MDA content (Table 2). Of interest, more recent study on patients with bronchial asthma, who also were characterized by indexes suggestive of oxidative stress, have shown that similar IHT produced the increase of superoxide dismutase (SOD) activity by nearly 70%. This increase correlated with a decrease in MDA content (r = -0.61, P< 0.05) (Safronova et al., 1999; Serebrovskaya et al., 1999c).

Thus studies in humans and in tissues have shown that adaptation to intermittent hypoxia induces increased antioxidant defenses, acceleration of electron transport in the respiratory chain, stabilization of cellular membranes, and Ca2+ elimination from the cytoplasm. These data served as the basis for IHT in the treatment of various diseases in which free-radical production might be anticipated, for example, bronchial asthma and post-Chernobyl syndromes.

Recent studies have shown the following principal results: (1) adaptation to intermittent hypobaric hypoxia stimulates NO production in the organism; (2) excessive NO synthesized in the course of adaptation is stored in the vascular wall; (3) adaptation to hypoxia prevents both NO over-production and NO deficiency, resulting in an improvement in blood pressure; and (4) effects of intermittent hypoxia on mitochondrial respiration are mediated mainly by NO-dependent reactions (Manukhina et al., 1999, 2000a,b; Malyshev et al., 2000; Ikkert et al., 2000; Smirin et al., 2000; Kurhalyuk and Serebrovskaya, 2001; Kurhalyuk et al., 2001b; Serebrovskaya et al., 2001).

A somewhat different hypothesis has also been suggested, that the electron transport function of the myocardial respiratory chain in the NAD-cytochrome-b area is limited to a greater extent in animals poorly tolerant to hypoxia than in those that are not. In intolerant animals, even mild hypoxia leads to diminution of the oxidative capacity of the respiratory chain and of ATP production and, as a consequence, to a suppression of the energy-dependent contractile function of the myocardium. In animals more tolerant of hypoxia, this process is less manifest and develops very slowly, which confirms the lesser role of NAD-dependent oxidation of substrates in the metabolism of the myocardium of these animals (Korneev et al., 1990).

Taken together these studies suggest that IHT induces increased ventilatory sensitivity to hypoxia in the absence of Pco2 or pH changes; that it induces other hypoxia-related physiological changes such as increased hematopoiesis and decreased plasma volume and increase in alveolar ventilation and lung diffusion capacity; and that it may be useful in the management of certain disease states. The effects appear to be mediated, at least in part, through release of reactive oxygen species, which then induce an increase of antioxidant defenses. In addition, IHT appears to induce changes within mitochondria, possibly involving NAD-dependent metabolism, that increase the efficiency of oxygen utilization in ATP production.

Response of skeletal muscle mitochondria to hypoxia

juni 23, 2013 av Marius

Alt om hvordan mitochondrier reagerer på hypoxi, inkludert under trening. Nevner ROS, kapillærer, oxygencascade, HIF-1,tibetanere og høydetreningmen ingen ting om CO2. Nevner også hypoxi inntrer 20s etter trening starter – ref HIIT.

http://ep.physoc.org/content/88/1/109.long

In contrast to earlier assumptions it is now established that permanent or long-term exposure to severe environmental hypoxia decreases the mitochondrial content of muscle fibres. Oxidative muscle metabolism is shifted towards a higher reliance on carbohydrates as a fuel, and intramyocellular lipid substrate stores are reduced. Moreover, in muscle cells of mountaineers returning from the Himalayas, we find accumulations of lipofuscin, believed to be a mitochondrial degradation product. Low mitochondrial contents are also observed in high-altitude natives such as Sherpas.

In these subjects high-altitude performance seems to be improved by better coupling between ATP demand and supply pathways as well as better metabolite homeostasis.

The hypoxia-inducible factor 1 (HIF-1) has been identified as a master regulator for the expression of genes involved in the hypoxia response, such as genes coding for glucose transporters, glycolytic enzymes and vascular endothelial growth factor (VEGF). HIF-1 achieves this by binding to hypoxia response elements in the promoter regions of these genes, whereby the increase of HIF-1 in hypoxia is the consequence of a reduced degradation of its dominant subunit HIF-1a.

A further mechanism that seems implicated in the hypoxia response of muscle mitochondria is related to the formation of reactive oxygen species (ROS) in mitochondria during oxidative phosphorylation. How exactly ROS interfere with HIF-1a as well as MAP kinase and other signalling pathways is debated.

The current evidence suggests that mitochondria themselves could be important players in oxygen sensing.

The focus on mitochondria neglects the fact that for the dominant function of mitochondria, aerobic ATP re-synthesis, the mitochondrial organelle cannot function independently. It is embedded, at least in animal phyla, in a systems physiological context. Mitochondria house the final biochemical steps in the production of reducing equivalents that react at the terminal oxidases of the respiratory chain with molecular oxygen provided by the respiratory system from the environment.

In mitochondria, O2 finally disappears and oxygen partial pressure goes to zero (Fig. 1). Mitochondria thus are an effective oxygen sink and this allows organisms to use all of the available oxygen partial pressure of the actual environment to drive the respiratory cascade from lungs through circulation to the mitochondria (Taylor & Weibel, 1981).

Figure 1

The pathway of oxygen. Simplified model of the oxygen transport pathway showing the principal structures and the corresponding partial pressure of oxygen (PJ) in these compartments, during maximal exercise, while breathing normoxic or hypoxic room air. mb, myoglobin. The data are derived from Richardson et al. (1995).

What is known is that isolated mitochondria do not need more than a few torr of O2 partial pressure for full function (Gayeski & Honig, 1997). Similarly, it is generally acknowledged that assessing mitochondrial function in hypoxia in cultured cells requires the lowering of the oxygen pressure at the cell surface to values between 0.5 and 5 Torr, values completely incompatible with the survival of all but a few highly specialized species (Boutilier & St Pierre, 2002).

In the context of this review we mostly neglect the hypoxic response of the microvasculature as well as the cardio- vascular and pulmonary system, which all conspire to maintain mitochondrial function under hypoxic conditions (Hochachka, 1998).

With ‘short- term’ hypoxia we refer to continuous bouts of hypoxia exposure lasting from minutes to hours (such as during a physical exercise bout), whereby during most of the day subjects are subjected to normoxic conditions.

With the term ‘intermittent’ hypoxia we designate experimental protocols whereby short periods of hypoxia (minutes) are interspersed with similarly short periods of normoxia. The physiological effects of inter- mittent hypoxia interventions have not yet been well defined. In particular, these types of interventions have not to our knowledge been analysed with regard to changes of the mitochondrial compartment. This literature will thus not be reviewed here (see Serebrovskaya, 2002).

One of the first notions of a change of muscle oxidative capacity with hypoxia is found in Reynafarje’s (1962) landmark paper on muscle adaptations in Peruvian miners. He found cytochrome c reductase activity (+78 %) and myoglobin content (+16%) to be significantly increased in biopsies of sartorius muscle of permanent high-altitude residents as compared to low-landers. This paper, together with data of larger muscle capillary densities in guinea pigs native to the Andeas as compared to data from low-land control animals (Valdivia, 1958), had a strong impact on physiologists’ thinking for at least two decades.

When it became clear towards the end of the sixties, that endurance-type exercise was also a potent stimulator of muscle mitochondrial enzyme activity (Holloszy, 1967), the connection was made that local tissue hypoxia provoked by exercise might be an important signal for mitochondrial proliferation under heavy exercise conditions.

The capillary density (i.e. the number of capillaries counted per unit area of muscle fibre) was indeed found to be increased in post-expedition samples. However, this was not due to capillary neo-formation since the capillary to muscle fibre ratio was unchanged. What had occurred over the time of the expedition was a significant loss of muscle fibre cross- sectional area. Hence, the same number of capillaries supplied a smaller tissue space. In addition, we found a decrease of mitochondrial volume density, which led to a total loss of muscle mitochondrial volume of close to 30 %.

This adaptation was suggested to represent an anti-apoptotic mechanism allowing protection against the lack of oxygen in oxidative muscles (Riva et al. 2001).

We would assume that the increased transcription of genes involved in the metabolic pathways favouring glucose metabolism in muscle cells is responsible for the observed shift towards glucose metabolism in organisms at altitude. The functional advantage of this adaptation would be a larger ATP yield per molecule of oxygen (Wilmore & Costill, 1994). It has recently been shown that protein expression of the enzymes and transporters of lactate, lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT1, 2 and 4), is affected in a tissue-specific manner by long-term exposure to hypobaric hypoxia (McClelland & Brooks, 2002). These findings are broadly compatible with the idea that hypoxia induces mechanisms favouring glucose utilization in muscle cells.

Despite the low muscle mitochondrial oxidative capacity, physical performance capacity of native high-land populations at altitude is excellent. A number of physiological mechanisms have been invoked to explain the ‘paradoxical’ finding of superior aerobic performance in hypoxia despite modest muscle oxidative capacities (Hochachka et al. 2002). Hochachka et al. (1998) describe systemic mechanisms, among them being a blunted hypoxia ventilatory and pulmonary vasoconstrictor response as well as an up-regulation of erythropoietin expression, which help native high-land populations to excel at altitude. At the level of muscle tissue it is suggested that the control contributions from cellular ATP demand and ATP supply pathways are up-regulated whereas the contribution of control steps in O2 delivery are down-regulated (Hochachka et al. 2002). This leads to an improved coupling between ATP demand and supply pathways and better metabolite (i.e. lactate, adenylates) homeostasis.

We thus decided to explore hypoxia protocols under which hypoxia was present only during the exercise session but not during recovery (e.g living low–training high). Analysis of pre- and post- training biopsies of m. vastus lateralis revealed that total mitochondria increased significantly in all groups; in contrast, subsarcolemmal mitochondria, i.e. those located near capillaries, increased significantly only in those groups training under hypoxic conditions, irrespective of training intensity. Noticeably, the group which trained at high intensity in hypoxia showed the highest increase in total mitochondrial volume density (+59 %) and capillary length density was increased significantly in this group only (+17.2 %) (Geiser et al. 2001; Vogt et al. 2001).

Several independent lines of evidence suggest the occurrence of ‘local hypoxia’, i.e. a drop in intramyocellular oxygen pressure with exercise.

This finding of a low muscle oxygen tension during exercise is supported by more recent data using 1H-nuclear magnetic resonance spectroscopy which demonstrates that myoglobin desaturation occurs within 20 s of onset of exercise in human quadriceps muscle (Richardson et al. 1995).

Mitochondria, the oxygen sink, are more prevalent in oxidative fibres by a factor of at least three, and even within fibres they are clustered in the fibre periphery close to the capillaries (Howald et al. 1985).

Figure 3
HIF-1a-mediated oxygen sensor and hypoxia-inducible gene expression. Oxygen stabilizes hypoxia- inducible factor 1a (HIF-1a) through Fe2+-dependent proline hydroxylases and asparaginyl hydroxylase(s) which hydroxylate HIF-1a within its oxygen-dependent degradation domain (ODDD) and C-terminal portion, respectively. Such modification causes recruitment of the von Hippel-Lindau tumour- suppressor protein (pVHL), which targets HIF-1a for proteosomal degradation thereby silencing HIF-1a activity. Conversely, hypoxia causes a stabilization of HIF-1a and activates the MAPK pathway which enhances the transcriptional activity of HIF-1a through phosphorylation. Both mechanisms contribute to transcriptional activation of downstream angiogenic factor (VEGF), erythropoietin (EPO), glucose transporters (glut 1 and 3) and glycolytic genes (PFK) via HIF-1a/HIF-1b dimers (HIF-1). Moreover, lack of oxygen (anoxia) causes HIF-1a stabilization, possibly by reducing the activity of hydoxylases by depleting their substrate O2.

In vitro experiments show that an activation of HIF-1 leads to an up-regulation of anaerobic enzymes of the glycolytic pathway (Wenger, 2002).

To date there is no clear-cut explanation for the paradoxical finding of increased reactive oxygen species (ROS) production in hypoxia as there is controversy about whether hypoxia, in fact, causes an increase or a fall in ROS production (Archer & Michelakis, 2002). Also the mechanisms by which ROS and cytosolic H2O2 levels are involved in stabilization/activation and eventual degradation/silencing of HIF-1a and other redox-sensitive transcription factors are controversially discussed (Chandel et al. 2000; Kietzmann et al. 2000).

It is reported that ~2% of the O2 used by the mitochondrial electron transport chain creates ROS and in particular the superoxide radical, due to its incomplete reduction (see Kietzmann et al. 2000; Archer & Michelakis, 2002; reviewed in Abele et al. 2002). The superoxide anion (O2•_) radical is very unstable and is rapidly converted either spontaneously or after its export into the cytoplasm by mitochondrial and cytoplasmic superoxide dismutases, MnSOD and Cu/ZnSOD, to the more stable H2O2.

Recent findings in hepatoma cells indicate a small (approximately 2.5-fold) and transient increase in ROS after 40–50 min of hypoxia onset (0.5 % O2; Vanden Hoek et al. 1998). These and subsequent in vitro experiments in the same system point to mitochondria, and to respiratory complex III of the electron transport chain in particular, as the source of ROS production in hypoxia (Chandel et al. 2000).

Figure 4

Targets of mitochondrial ROS production. Incomplete reduction of O2 during normal metabolic conversion of pyruvate in mitochondria gives rise to a low level of superoxide anion (O2•_). Exposure of cells to hypoxia increases the aberrant production of O2•_ at the mitochondrial electron chain complex III. Catalysed or spontaneous dismutation of the unstable superanion and export via anion channels enhances the concentration of cytosolic H2O2 and other reactive oxygen species (ROS). Increased ROS may increase the level of oxidatively damaged lipids (lipofuscin) or activate downstream redox-sensitive signal transduction events. For example ROS stabilize HIF-1a possibly by interfering with the activity of Fe2+-dependent proline hydroxylases. ROS may also activate the MAPK or PI-3K/Akt pathway, which enhance the transcriptional activity of HIF-1a through its phosphorylation. Lastly, mechanical stress may also increase ROS production which may influence HIF-1a activation.

Clearly there is evidence pointing to a role of mitochondria as oxygen sensors by modulation of ROS production.

Recently, evidence for increased oxidant production in rat skeletal muscle during prolonged exercise has been provided, with both the mitochondrial respiratory chain and the NADPH oxidase as potential sources for oxidants (Bejma & Ji, 1999). This argues for ROS production in skeletal muscle due to local tissue hypoxia.

Two routes to functional adaptation: Tibetan and Andean high-altitude natives

juni 22, 2013 av Marius

Om hvordan pusten endres når man bor i høyland. Nevner mye om oksygentilgjengelighet, oksygenkaskade, hypoxi, kapillærer, mitokondrier, m.m., og om hvorfor vi har lite oksygen i mitokondriene. Studier undersøker spesifikt om at tibetanere har endrede gener siden de med gener som er tilpasset lave oksygennivåer har mindre fysiologisk stress og dermed større sjangse for barn som overlever, og hvilke forkjeller i hypoxi-tilpasning som har sjedd i de to befolkningene.

Ny, som må gjennomgåes: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876443/

http://www.pnas.org/content/104/suppl.1/8655.full

These reveal generally more genetic variance in the Tibetan population and more potential for natural selection. There is evidence that natural selection is ongoing in the Tibetan population, where women estimated to have genotypes for high oxygen saturation of hemoglobin (and less physiological stress) have higher offspring survival.

At 4,000-m elevation, every breath of air contains only ≈60% of the oxygen molecules in the same breath at sea level. This is a constant feature of the ambient environment to which every person at a given altitude is inexorably exposed. Less oxygen in inspired air results in less oxygen to diffuse into the bloodstream to be carried to the cells for oxygen-requiring energy-producing metabolism in the mitochondria.

Humans do not store oxygen, because it reacts so rapidly and destructively with other molecules. Therefore, oxygen must be supplied, without interruption, to the mitochondria and to the ≥1,000 oxygen-requiring enzymatic reactions in various cells and tissues (4).

Fig. 1. Ambient oxygen levels, measured by the partial pressure of oxygen (solid line) or as a percent of sea-level values (dashed line), decrease with increasing altitude, a situation called high-altitude or hypobaric hypoxia. The atmosphere contains ≈21% oxygen at all altitudes.

The oxygen level is near zero in human mitochondria at all altitudes (5). This condition is described as “primitive,” because it has changed little for the past 2.5 billion years despite wide swings in the amount of atmospheric oxygen (at times it has been 10,000-fold lower; refs. 6 and 7) and “protective” in the sense that it circumvents potentially damaging reactions of oxygen with other molecules (8).

Fig. 2. The oxygen transport cascade at sea level (solid line) and at the high altitude of 4,540 m (dashed line) illustrates the oxygen levels at the major stages of oxygen delivery and suggests potential points of functional adaptation (data from ref. 60).

Potential and Actual Points of Adaptation to Hypoxia

Energy Production.

Lowlanders traveling to high altitude display homeostatic responses to the acute severe hypoxia. The responses are energetically costly, as indicated by an increase in basal metabolic rate (BMR; the minimum amount of energy needed to maintain life with processes such as regulating body temperature, heart rate, and breathing). BMR is increased by ≈17–27% for the first few weeks upon exposure to high altitude and gradually returns toward sea-level baseline (9). In other words, for acutely exposed lowlanders, the fundamental physiological processes required to sustain life at high altitude require more oxygen despite lower oxygen availability.

In contrast to acutely exposed lowlanders and despite the equally low level of oxygen pressure in the air and lungs, both Andean and Tibetan highlanders display the standard low-altitude range of oxygen delivery from minimal to maximal. Both populations have the normal basal metabolic rate expected for their age, sex, and body weight (14–16), implying that their functional adaptations do not entail increased basal oxygen requirements. Furthermore, Andean and Tibetan highlanders have maximal oxygen uptake expected for their level of physical training (12, 13, 17).

Ventilation.

One potential point of adaptation in oxygen delivery is ventilation, which, if raised, could move a larger overall volume of air and achieve a higher level of oxygen in the alveolar air (Fig. 2) and diffusion of more oxygen. An immediate increase in ventilation is perhaps the most important response of lowlanders acutely exposed to high altitude, although it is not sustained indefinitely and is not found among members of low-altitude populations born and raised at high altitude, such as Europeans or Chinese (3, 18).

For example, a comparative analysis summarizing the results of 28 samples of Tibetan and Andean high-altitude natives at an average altitude of ≈3,900 m reported an estimated resting ventilation of 15.0 liters/min among the Tibetan samples as compared with 10.5 liters/min among the Andean samples (19).

Fig. 3 illustrates the higher resting ventilation of Tibetans as compared with Andean highlanders evaluated using the same protocol at ≈4,000 m. The mean resting ventilation for Tibetans was >1 SD higher than the mean of the Andean highlanders (20).

Oxygen in the Bloodstream.

The higher ventilation levels among Tibetans that move more oxygen through the lungs, along with the higher HVRs that respond more vigorously to fluctuations in oxygen levels, might be expected to result in more oxygen in the bloodstream. However, the level of oxygen in the arterial blood (Fig. 2) of a sample of Tibetans at ≈3,700 m was lower than that of a sample of Andean high-altitude natives at the same altitude (54 as compared with 57 mmHg; 1 mmHg = 133 Pa) (24, 25). In addition, hemoglobin, the oxygen-carrying molecule in blood, is less saturated with oxygen among Tibetans than among their Andean counterparts (26, 27). Fig. 3 illustrates the lower percent of oxygen saturation of hemoglobin in a sample of Tibetans at ≈4,000 m. The increased breathing of Tibetans does not deliver more oxygen to the hemoglobin in the arteries.

Fig. 3 illustrates the markedly lower hemoglobin concentrations in a sample of Tibetan men and women as compared with their Andean counterparts at ≈4,000 m. [The average hemoglobin concentrations were 15.6 and 19.2 g/dl for Tibetan and Andean men, respectively, and 14.2 and 17.8 g/dl for women (28).] Hemoglobin concentration is influenced by many factors, including erythropoietin, a protein that causes differentiation of the precursors that will become hemoglobin-containing red blood cells. Tibetans have slightly lower erythropoietin concentrations than Andean highlanders at the same altitude (25). When matched for volume of red blood cells, a procedure that would effectively compare the highest Tibetan and the lowest Andean values, Andean highlanders have much higher erythropoietin levels, which implies that some sensor is responding as if the stress were more severe, even though the samples were collected at the same altitude of ≈3,700 m.

Andean highlanders have overcompensated for ambient hypoxia according to this measure, whereas Tibetan highlanders have undercompensated. Indeed, Tibetans are profoundly hypoxic and must be engaging other mechanisms or adapting at different points in the oxygen transport cascade to sustain normal aerobic metabolism.

Fig. 4. The calculated arterial oxygen content of Tibetan men and women is profoundly lower than their Andean counterparts measured at ≈4,000 m (data from ref. 62), whereas the exhaled NO concentration is markedly higher (recalculated from data reported in ref. 34).

Blood Flow and Oxygen Diffusion.

Other potential points of functional adaptation include the rate of flow of oxygen-carrying blood to tissues and the rate of oxygen diffusion from the bloodstream into cells.

Because blood flow is a function of the diameter of blood vessels, dilating factors could, in principle, improve the rate of oxygen delivery. Sea-level populations respond to high-altitude hypoxia by narrowing the blood vessels in their lungs, the first point of contact with the circulation. Known as hypoxic pulmonary vasoconstriction, that reflex evolved at sea level to direct blood away from temporarily poorly oxygenated toward better oxygenated parts of the lung. High-altitude hypoxia causes poor oxygenation of the entire lung and general constriction of blood vessels to the degree that it raises pulmonary blood pressure, often to hypertensive levels (3, 29).

In contrast, most Tibetans do not have hypoxic pulmonary vasoconstriction or pulmonary hypertension. This is indicated by essentially normal pulmonary blood flow, as measured by normal or only minimally elevated pulmonary artery pressure (29, 30).

a mean pulmonary artery pressure of 31 mmHg for the Tibetan 28% lower than the mean of 43 mmHg for the Andean (35 mmHg is often considered the upper end of the normal sea-level range) (30, 31). Andean highlanders are consistently reported to have pulmonary hypertension (29). Thus, pulmonary blood flow is another element of oxygen delivery for which Tibetans differ from Andean highlanders in the direction of greater departure from the ancestral response to acute hypoxia.

A probable reason for the normal pulmonary artery pressure among Tibetans is high levels of the vasodilator nitric oxide (NO) gas synthesized in the lining of the blood vessels. Low-altitude populations acutely exposed to high-altitude down-regulate NO synthesis, a response thought to contribute to hypoxic pulmonary vasoconstriction (32, 33). In contrast, NO is substantially elevated in the lungs of Tibetan as compared with Andean highlanders and lowlanders at sea level (Fig. 4) (34). Among Tibetans, higher exhaled NO is associated with higher blood flow through the lungs (30).

Several other lines of evidence highlight the importance of high blood flow for Tibetans. These include greater increase in blood flow after temporary occlusion (35) and higher blood flow to the brain during exercise (36) as compared with lowlanders.

Generally, Tibetans appear to have relatively high blood flow that may contribute significantly to offsetting their low arterial oxygen content.

A denser capillary network could potentially improve perfusion and oxygen delivery, because each capillary would supply a smaller area of tissue, and oxygen would diffuse a shorter distance. Tibetans (the study sample were Sherpas, an ethnic group that emigrated from Tibet to Nepal ≈500 years ago) who are born and raised at high altitude have higher capillary density in muscles as compared with Andean high-altitude natives, Tibetans born and raised at low altitude, or lowlanders (Fig. 5) (40).

Fig. 5. High-altitude native Tibetans have higher capillary density than their Andean counterparts or populations at low altitude; Tibetan and Andean highlanders both have lower mitochondrial volume than low-altitude populations (data from refs. 40, 44, 63, and64).

The last potential point of adaptation is at the level of the mitochondrion itself. Acutely exposed lowlanders lose mitochondria in leg muscles during the first 3 weeks at altitude. Similarly, both Tibetan (Sherpas) and Andean high-altitude natives have a lower mitochondrial volume in leg muscle tissue than sea-level natives at sea level (Fig. 5) (40).

Among Tibetans, a smaller mitochondrial volume somehow supports a relatively larger oxygen consumption, perhaps by higher metabolic efficiency (12, 43, 44).

Another candidate gene is the transcription factor hypoxia-inducible factor 1 (HIF1) often called the “master regulator” of oxygen homeostasis, because it induces >70 genes that respond to hypoxia (56–58). An investigation of polymorphisms in the HIF1A gene of Tibetans (Sherpas) found a dinucleotide repeat in 20 Tibetans that was not found in 30 Japanese lowlander controls (59).

Differences in the control of breathing between Himalayan and sea-level residents

juni 21, 2013 av Marius

Om hvordan langvarig høydeopphold utvisker sensitiviteten til CO2.

http://jp.physoc.org/content/588/9/1591.full

Highlanders had lower mean ± S.E.M.ventilatory sensitivities to CO2 than lowlanders at both isoxic tensions (hyperoxic: 2.3 ± 0.3 vs. 4.2 ± 0.3 l min−1 mmHg−1, P = 0.021; hypoxic: 2.8 ± 0.3 vs. 7.1 ± 0.6 l min−1mmHg−1, P < 0.001), and the usual increase in ventilatory sensitivity to CO2 induced by hypoxia in lowlanders was absent in highlanders (P = 0.361).

Furthermore, the ventilatory recruitment threshold (VRT) CO2 tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 ± 0.9 vs. 48.9 ± 0.7 mmHg, P < 0.001; hypoxic: 31.2 ± 1.1 vs. 44.7 ± 0.7 mmHg, P < 0.001).

We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea-level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO2. Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO2-independent increase in activity of peripheral chemoreceptor or hypoxia-induced increase in [H⁺] at the central chemoreceptor.

Control of breathing in humans can be broadly divided into chemoreflex and non-chemoreflex drives to breathe (Fig. 1) (Lloyd & Cunningham, 1963). Non-chemoreflex breathing stimuli include a wakefulness drive (Longobardo et al. 2002), voluntary (cortical) drive (Shea, 1996) and hormonal factors (Jensen et al. 2008), as well as neural and humoral mediating factors that are especially important in the control of breathing during exercise (Bell, 2006; Dempsey, 2006; Haouzi, 2006). The chemoreflex drive to breathe can be further divided into central and peripheral chemoreceptor drives. Both central and peripheral chemoreceptors respond to changes in the hydrogen ion concentration ([H⁺]) in their immediate environments (Torrance, 1996; Nattie & Li, 2009).

In contrast to the central chemoreceptors, peripheral chemoreceptors are also sensitive to changes in arterial () via a hypoxia-mediated increase in their sensitivity to [H⁺] (Cunningham, 1987; Torrance, 1996; Kumar & Bin-Jaliah, 2007), and hyperoxia ( ≥ 150 mmHg) effectively silences this response (Lloyd & Cunningham, 1963; Mohan & Duffin, 1997).

Central and peripheral chemoreceptor neural drives are integrated in the medulla to provide the total chemoreflex neural drive (Fink, 1961; Shea, 1996; Mohan & Duffin, 1997; Orem et al. 2002) that, in combination with non-chemoreflex drives, provides ventilatory drive to respiratory muscles.

Figure 3. Hypercapnic ventilatory response The graph displays two isoxic responses: hyperoxic ( = 150 mmHg) representing central chemoreflex response, and hypoxic ( = 50 mmHg) representing the addition of central and peripheral chemoreflexes responses. The slope of each isoxic response represents sensitivity of the chemoreflex to CO2. The inflection point at which ventilation starts to increase in response to increasing is the ventilatory recruitment threshold (VRT), where the chemoreflex neural drive to breathe exceeds a drive threshold and starts to produce an increase in pulmonary ventilation. Ventilation below VRT represents non-chemoreflex drives to breathe and is known as the basal ventilation. The differences in ventilation between isoxic rebreathing lines at any given isocapnic can be used to calculate the hypoxic ventilatory response (indicated by vertical arrows). Note that the choice of isocapnic affects the magnitude of the measured HVR even within the same subject (Duffin, 2007), with higher HVRs measured at higher isocapnic values in the illustrated example. Note also that the magnitude of HVR provides little information about the characteristics of the control of breathing model, as HVR magnitude is dependent on the combination of central and peripheral chemoreflex responses.

There was no difference in the non-chemoreflex drives to breathe between highlanders and lowlanders, as indicated by similar basal (below VRT) ventilations in the two populations (Table 2).

The highlanders had decreased VRTs compared to lowlanders during both hypoxic and hyperoxic rebreathing tests. The leftward shift of the VRTs in highlanders suggests that a lower was required to exceed the VRT in highlanders compared to lowlanders. Since both central and peripheral chemoreceptors are actually [H⁺] sensors, interpretation of this result should consider the acid–base status in both populations. According to the Henderson–Hasselbach equation (Nunn, 1993), the relationship between [H⁺] and can be described as follows: Formula where [HCO₃⁻] is the bicarbonate ion concentration. In a hypothetical sea-level resident at sea-level, [H⁺] is approximately 40 nM l−1, is 40 mmHg and [HCO₃⁻] is 24 mM l−1. At altitude, hypoxia-induced hyperventilation results in a reduction of that leads to a reduction in [H⁺] and respiratory alkalosis according to the above equation. Highlanders compensate for respiratory alkalosis by presumably reducing their [HCO₃⁻] through increased renal excretion, thereby restoring the /[HCO₃⁻] ratio to sea-level values and normalizing [H⁺].

For example, if hypoxia-induced hyperventilation reduced CO2 from 40 to 30 mmHg, and HCO3− fell from 24 to 18 mM l−1, then the overall ratio of CO2/HCO3− would be maintained at 5/3 as in sea-level lowlanders, but normal [H⁺] of 40 nM l−1 would be achieved at a lower of 30 mmHg rather than 40 mmHg, as at sea-level. Considering that the highlanders in our study have an adapted acid–base status (Santolaya 1989), the observed difference in VRTs can be explained by the altered [H⁺]– relationship in highlanders compared to lowlanders, with the assumption that the chemoreceptor thresholds [H⁺] are similar (Duffin, 2005).

The sensitivity of the central chemoreceptor to CO2, as indicated by the ventilatory sensitivity during hyperoxic rebreathing, was lower in highlanders compared to lowlanders (2.5 ± 0.4 vs. 4.2 ± 0.3 l min−1 mmHg−1, P = 0.011). Hyperoxia effectively silences the peripheral chemoreceptor (Lloyd & Cunningham, 1963; Mohan & Duffin, 1997), and therefore the ventilatory sensitivity measured during hyperoxic rebreathing can be taken as a measure of central chemoreceptor sensitivity (Duffin, 2007).

Since the ventilatory response to hypercapnia decreases with age (Nishimura et al. 1991; Jones et al. 1993; Poulin et al.1993; McGurk et al. 1995) and increases with weight (Marcus et al. 1994), the observed lower central CO2 chemosensivity in our highlander subjects may be the result of their older age and smaller body size.

Ventilatory response to hypoxia in highlanders was markedly different from that in lowlanders. Unlike lowlanders, who responded to hypoxia by increasing the sensitivity of their ventilatory response to CO2 (Mohan & Duffin, 1997), the highlanders seemed to decrease their VRT in response to hypoxia with no change in the sensitivity to CO2.

The ventilatory response to hypoxia in sea-level residents is mediated by peripheral chemoreceptors via an increase in the peripheral chemoreceptor sensitivity to [H⁺] (Cunningham, 1987; Torrance, 1996; Kumar & Bin-Jaliah, 2007). A lack of increase in ventilatory sensitivity to CO2 with induction of hypoxia in highlanders suggests that their peripheral chemoreceptors are relatively insensitive to CO2.

Other possible mechanisms of CO2-independent peripheral responses to hypoxia may include a hypoxia-induced increase in the carotid body tonic drive to breathe, changes in systemic hormonal mediators, an altered cerebral spinal fluid-buffering capacity at the central chemoreceptor or an alteration in cerebral vascular reactivity leading to a higher [H⁺] at central chemoreceptor.

Specifically, we showed that Himalayan highlanders have decreased central and absent peripheral chemoreceptor sensitivity to CO2, and that they are sensitive to hypoxia, albeit via a different mechanism than that observed in lowlanders at sea-level. A blunted central and an absent peripheral ventilatory sensitivity to CO2 in Himalayan highlanders may stabilize their ventilatory controller by reducing the overall gain in the feedback part of the controller circuit, thereby reducing altitude-related breathing instability (Ainslie & Duffin, 2009)

The non-chemoreflex drives to breathe were similar between Himalayan highlanders and sea-level lowlanders.

Effects of Slow Deep Breathing at High Altitude on Oxygen Saturation, Pulmonary and Systemic Hemodynamics

juni 21, 2013 av Marius

Om hvordan sakte pust øker oksygennivå når man er på høyfjellet.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495772/

Study variables, including SpO2 and systemic and pulmonary arterial pressure, were assessed before, during and after 15 minutes of breathing at 6 breaths/min. At the end of slow breathing, an increase in SpO2 (Study A: from 80.2±7.7% to 89.5±8.2%; Study B: from 81.0±4.2% to 88.6±4.5; both p<0.001) and significant reductions in systemic and pulmonary arterial pressure occurred. This was associated with increased tidal volume and no changes in minute ventilation or pulmonary CO diffusion

From the point of view of oxygen gas exchange, human lungs are highly inefficient, as suggested by the 50–60 mmHg PO2 gap between atmosphere and arterial blood observed at sea level. Indeed, some animal species can reach much higher altitudes than humans without supplement O2 due to several reasons including a lower PO2 gap between atmosphere and arterial blood

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Destroy user interface control [1].

In turn, hypoxemia activates a chemoreflex response leading to increased ventilation, which results in hypocapnia and respiratory alkalosis. Exposure to HA is also associated with pulmonary hypertension and lung fluid accumulation, both of which further contribute to hypoxemia and, in some cases, lead to high altitude pulmonary edema (HAPE)

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Destroy user interface control [2],

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Destroy user interface control [3].

Efficiency of ventilation for oxygen may be improved by changing the respiratory pattern in order to optimize the partitioning between alveolar ventilation and airway ventilation, being that the latter useless in terms of gas exchange. This has been reported by Yoga practice

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Destroy user interface control [4] or by regular breathing as obtained during regular rosary praying

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Controlled breathing with low rate and high tidal volume, the so called “slow deep breathing”, has also been shown to improve the efficiency of ventilation by increasing alveolar and reducing dead space ventilation

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Destroy user interface control [6]. Slow deep breathing may also improve arterial oxygenation by increasing alveolar volume and gas exchange at the alveolar capillary membrane level. The latter particularly increases when interstitial lung fluids are increased. Indeed, it has been reported that paced slow deep breathing improves blood oxygenation in subjects chronically exposed to HA

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Destroy user interface control [7] and in patients with congestive heart failure or with chronic pulmonary obstructive disease

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Destroy user interface control [6],

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Destroy user interface control [8],

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Destroy user interface control [10]. Slow deep breathing might also counteract some hemodynamic effects of hypobaric hypoxia at HA, including the increase in systemic blood pressure

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Destroy user interface control [11], given the evidence that device-guided slow deep breathing reduces elevated blood pressure in hypertensive patients

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Destroy user interface control [12],

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495772/bin/pone.0049074.g002.jpg

Our main result is that in healthy subjects exposed to HA, i.e. to a low ambient-air PO2, the change in breathing pattern from a spontaneous rate to a paced frequency of 6 breaths per minute was associated with an improvement of ventilation efficiency, as shown by the significant increase in blood oxygen saturation. This was the case both for acute (Study A) and prolonged (Study B) exposure to HA hypoxia. This increase occurred rapidly and was maintained throughout the slow deep breathing period. Most of the improvement of blood oxygenation was lost within 5 minutes after restoration of spontaneous breathing pattern, and no differences compared with baseline were evident after 30 minutes.

In the present study, we showed for the first time the time course of the response to slow deep breathing, showing that the maximum effect is reached after about 5 minutes and is subsequently maintained. Moreover, we reported for the first time data on the recovery period. In Study B, we extended the recovery period to 30 minutes, which allowed us to observe a progressive reduction of slow deep breathing effects, which are at their highest after 5 minutes, but some continue up to 30 minutes after its termination.

However, the reduction of PtCO2 during slow deep breathing exercise in Study A and the SpO2increase in both studies suggest that slow deep breathing improves the efficiency of ventilation. The lack of reduction of PetCO2 in Study B (table 1) is not in contrast with this interpretation of our findings but merely a technical consequence of the measurement technique.

Indeed, PetCO2 pressure, due to the shape of the CO2 curve during expiration, is higher with lower respiratory frequency. Therefore, a reduction in PaCO2 may actually have occurred during slow deep breathing in both studies.

Moreover, because slow deep breathing is associated to a reduction of sympathetic tone (see below), the improvement of ventilation/perfusion matching may also originate by more respiratory sinus arrhythmia

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Destroy user interface control [22]. Finally, the reduction of sympathetic tone could lead to a reduction in metabolic rate, which, possibly combined with an increase of cardiac output, may lead to an increase of mixed venous PO2 and thus less admixture. All together, our data suggest that the benefits from slow deep breathing exercise are due to an improvement in ventilation mechanics, in pulmonary perfusion and in ventilation/perfusion matching, and possibly to a reduction of the metabolic rate.

This acute blood pressure lowering effect of slow deep breathing may be related to the ability of this manoeuvre to increase baroreflex and reduce chemoreflex sensitivity

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Destroy user interface control [23], resulting in a sympathetic inhibitory action, as recently directly shown by Oneda et al.

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The blood pressure reduction observed in our study is in line with data obtained in previous studies that proposed regular and repeated performance of slow deep breathing exercise at sea level as a nonpharmacological approach to the treatment of hypertension

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Destroy user interface control [14]. These studies have also emphasized that this effect may originate from an enhanced sensitivity of the baroreflex and/or a reduced sensitivity of the chemoreflex

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In conclusion, slow deep breathing induced a significant improvement in ventilation efficiency as shown by SpO2 increase in healthy subjects exposed to HA. This improvement was most likely due to a reduction of dead space ventilation and an increase in alveolar ventilation, and was associated to a reduction of both pulmonary and systemic BP levels, both elevated at HA. This intervention is easy and cheap.

Physiological Sensing of Carbon Dioxide/Bicarbonate/pH via Cyclic Nucleotide Signaling

juni 20, 2013 av Marius

Viktig studie som viser hva som skjer med CO2 og hvordan det regulerer forskjellige prosesser. Blodsirkulasjon nevnes også.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085406/

Carbon dioxide (CO2) and water are the major end products of energy producing pathways in living organisms (Equation (1)). As such, in non-photosynthetic organisms, CO2 and water represent the most fundamental catabolites.

Glucose (or other energy sources) + O2

Fibromyalgia is not all in your head, new research confirms

juni 20, 2013 av Marius

Interessant bilde som viser hvordan sympaticus nerver stenger «shunts» i huden for å øke blodsirkulasjon til huden og avgi varme, mens sensoriske nerver åpner «shunts» slik at blodsirkulasjonen til huden minker og vi kan bevare varme. I fibromyalgi har forskere funnet at sensoriske nerver holder «shunts» åpne slik at blodsirkulasjonen i huden minker, dette gir kalde hender og bidrar til smerte. Nevner at hender og føtter er et «reservoir» av blod som kan påvirke blodsirkulasjonen i hele resten av kroppen.

http://medicalxpress.com/news/2013-06-fibromyalgia.html

This schematic illustrates the organization of blood vessels and the regulation of blood flow (arrows) in the palm of the hands. Arteriole-venule shunts are small muscular valves that connect directly between an arteriole and a venule to bypass the capillaries. Arrows indicate the direction of blood flow. As shown on the left, in order to radiate heat from our skin when we are hot, activation of the sympathetic nerve fibers close the shunts so that oxygenated blood (red arrows) in the arterioles is forced into the capillaries and deoxygenated (blue arrows) blood returns to the venules. As shown to the right, in order to conserve heat when we are cold, activation of sensory nerve fibers dilate the shunts and the blood bypasses the capillaries. Fibromyalgia patients were found to have an excessive amount of sensory fibers around the shunts.

Dr. Rice continued, «We previously thought that these nerve endings were only involved in regulating blood flow at a subconscious level, yet here we had evidencs that the blood vessel endings could also contribute to our conscious sense of touch… and also pain.»

As Dr. Rice describes their function, «We are all taught that oxygenated blood flows from arterioles to capillaries, which then convey the deoxygenated blood to the venules. The AV shunts in the hand are unique in that they create a bypass of the capillary bed for the major purpose of regulating body temperature.»

«In addition to involvement in temperature regulation, an enormous proportion of our blood flow normally goes to our hands and feet. Far more than is needed for their metabolism» noted Dr. Rice. «As such, the hands and the feet act as a reservoir from which blood flow can be diverted to other tissues of the body, such as muscles when we begin to exercise. Therefore, the pathology discovered among these shunts in the hands could be interfering with blood flow to the muscles throughout the body. This mismanaged blood flow could be the source of muscular pain and achiness, and the sense of fatigue which are thought to be due to a build-up of lactic acid and low levels of inflammation fibromyalgia patients. This, in turn, could contribute to the hyperactvity in the brain.»

Pain

juni 18, 2013 av Marius

Svært viktig studie med alt om smerte, fra Melzaks Body-Self Neuromatrix. Smerteforståelsens historie, fantomsmerter, hypersensitivitet, nervedegenerasjon, betennelser, Gate Control og Neuromatrix teori, m.m. Her forklares hvordan kroppsopplevelsen skapes i hjernen, selv uten noen input fra kroppen. Nevner også at smerte kan sette seg som et minne; somatic memory. Og vier mye plass til hvordan stress og kortisol bidrar til kroniske smerter, muskelsvikt og nedsatt immunsystem.

http://onlinelibrary.wiley.com/doi/10.1002/wcs.1201/full

Smerte har en funksjon i menneskekroppen som har utviklet seg i evolusjonen for å holde oss i live. Det gjør at vi tilpasser vår aktivitet så kroppen kan fokusere på helbredelse.

Pain has many valuable functions. It often signals injury or disease, generates a wide range of adaptive behaviors, and promotes healing through rest.

Men de siste 100-årenes (og foreløpige) forståelse av selve årsaken til smerte, hvordan den oppstår og hvordan den forsvinner, er basert på et mekanisk kroppsbilde som ikke tar hensyn til den subjektive smerteopplevelse. Melsaks arbeid viser oss hvordan vi snur dette og får en bedre og mer korrekt forståelse av smertefunksjonen:

Pain is a personal, subjective experience influenced by cultural learning, the meaning of the situation, attention, and other psychological variables. Pain processes do not begin with the stimulation of receptors. Rather, injury or disease produces neural signals that enter an active nervous system that (in the adult organism) is the substrate of past experience, culture, and a host of other environmental and personal factors.

Pain is not simply the end product of a linear sensory transmission system; it is a dynamic process that involves continuous interactions among complex ascending and descending systems. The neuromatrix theory guides us away from the Cartesian concept of pain as a sensation produced by injury, inflammation, or other tissue pathology and toward the concept of pain as a multidimensional experience produced by multiple influences.

Smerte er en helbredelsesfunksjon. Den hjelper oss å unngå truende situasjoner og sørger for at vi gir kroppen mulighet til å helbrede seg. Det er en naturlig og intelligent biologisk funksjon som i milliarder av år igjennom evolusjonen har sørget for at vi overlever så lenge som mulig.

We all know that pain has many valuable functions. It often signals injury or disease and generates a wide range of behaviors to end it and to treat its causes. Chest pain, for example, may be a symptom of heart disease, and may compel us to seek a physician’s help. Memories of past pain and suffering also serve as signals for us to avoid potentially dangerous situations. Yet another beneficial effect of pain, notably after serious injury or disease, is to make us rest, thereby promoting the body’s healing processes. All of these actions induced by pain—to escape, avoid, or rest—have obvious value for survival.

Smerteproblematikk har eksplodert de siste 20-30 årene og korsryggsmerter har overtatt plassen fra sult som den viktigste årsaken til ubehag blandt verdens befolkning. Melzak foreslår at vi bør se på kronisk smerte som en sykdom i seg selv, ikke som et symptom. En sykdom som følge av at nervesystemets alarm-mekanismer har slått seg vrang.

The pain, not the physical impairment, prevents them from leading a normal life. Likewise, most backaches, headaches, muscle pains, nerve pains, pelvic pains, and facial pains serve no discernible purpose, are resistant to treatment, and are a catastrophe for the people who are afflicted.

Pain may be the warning signal that saves the lives of some people, but it destroys the lives of countless others. Chronic pains, clearly, are not a warning to prevent physical injury or disease. They are the disease—the result of neural mechanisms gone awry.1–3

A BRIEF HISTORY OF PAIN

I smerteforskning og forståelse har vi, siden Descartes tid på 1600-tallet, beveget oss fra utsiden av kroppen igjennom det vi trodde var smerte-nervetråder, inn til ryggmargens «Gate Control», og nå, med The Neuromatrix, kommet opp til selve hjernen hvor vår opplevde virkelighet faktisk skapes. Først nå de siste årene har vi begynt å inkludere hjernens forskjellige funksjoner og dens eget «bilde» og opplevelse av kroppen. Tidligere ville pasienter som ikke ble bedre av kirurgi eller behandling bare bli avfeid av legene og heller sent til psykolog, hvor de heller ikke fikk noe spesifikk hjelp for smertene. Først nå, endelig, kan behandling av kronisk smerte inkludere større deler av mennesket som stemmer bedre overens med realiteten i både den subjektive opplevelsen og den vitenskapelige forklaringsmodellen.

The theory of pain we inherited in the 20th century was proposed by Descartes three centuries earlier. The impact of Descartes’ specificity theory was enormous. It influenced experiments on the anatomy and physiology of pain up to the first half of the 20th century (reviewed in Ref 4). This body of research is marked by a search for specific pain fibers and pathways and a pain center in the brain. The result was a concept of pain as a specific, direct-line sensory projection system. This rigid anatomy of pain in the 1950s led to attempts to treat severe chronic pain by a variety of neurosurgical lesions. Descartes’ specificity theory, then, determined the ‘facts’ as they were known up to the middle of the 20th century, and even determined therapy.

Specificity theory proposed that injury activates specific pain receptors and fibers which, in turn, project pain impulses through a spinal pain pathway to a pain center in the brain. The psychological experience of pain, therefore, was virtually equated with peripheral injury. In the 1950s, there was no room for psychological contributions to pain, such as attention, past experience, anxiety, depression, and the meaning of the situation.

Patients who suffered back pain without presenting signs of organic disease were often labeled as psychologically disturbed and sent to psychiatrists.

However, in none of these theories was there an explicit role for the brain other than as a passive receiver of messages. Nevertheless, the successive theoretical concepts moved the field in the right direction: into the spinal cord and away from the periphery as the exclusive answer to pain. At least the field of pain was making its way up toward the brain.

(D) Gate control theory. The large (L) and small (S) fibers project to the substantia gelatinosa (SG) and first central transmission (T) cells. The central control trigger is represented by a line running from the large fiber system to central control mechanisms, which in turn project back to the gate control system. The T cells project to the entry cells of the action system. +, excitation; −, inhibition.

THE GATE CONTROL THEORY OF PAIN

The Gate Control beskriver hvordan stimulering av store nervefibre, f.eks. å blåse på sår, stryke på huden, osv., (mekanoreseptorer i huden) kan overdøve smertesignalene som kommer fra små nervefibre (nociceptive C-fibre). Gate Control teorien var den første som viste hvordan sentralnervesystemet kunne nedregulere smerte ovenifra og ned. Som inkluderer hjernens respons på signalene fra kroppen.

The final model, depicted in Figure 1(d), is the first theory of pain to incorporate the central control processes of the brain.

The gate control theory of pain11 proposed that the transmission of nerve impulses from afferent fibers to spinal cord transmission (T) cells is modulated by a gating mechanism in the spinal dorsal horn. This gating mechanism is influenced by the relative amount of activity in large- and small-diameter fibers, so that large fibers tend to inhibit transmission (close the gate) while small-fibers tend to facilitate transmission (open the gate).

When the output of the spinal T cells exceeds a critical level, it activates the Action System—those neural areas that underlie the complex, sequential patterns of behavior and experience characteristic of pain.

Psychological factors, which were previously dismissed as ‘reactions to pain’, were now seen to be an integral part of pain processing and new avenues for pain control by psychological therapies were opened.

BEYOND THE GATE

We believe the great challenge ahead of us is to understand brain function. Melzack and Casey13 made a start by proposing that specialized systems in the brain are involved in the sensory-discriminative, motivational-affective and cognitive-evaluative dimensions of subjective pain experience (Figure 2).

Figure 2. Conceptual model of the sensory, motivational, and central control determinants of pain. The output of the T (transmission) cells of the gate control system projects to the sensory-discriminative system and the motivational-affective system. The central control trigger is represented by a line running from the large fiber system to central control processes; these, in turn, project back to the gate control system, and to the sensory-discriminative and motivational-affective systems. All three systems interact with one another, and project to the motor system.

The newest version, the Short-Form McGill Pain Questionnaire-2,16 was designed to measure the qualities of both neuropathic and non-neuropathic pain in research and clinical settings.

In 1978, Melzack and Loeser17 described severe pains in the phantom body of paraplegic patients with verified total sections of the spinal cord, and proposed a central ‘pattern generating mechanism’ above the level of the section. This concept represented a revolutionary advance: it did not merely extend the gate; it said that pain could be generated by brain mechanisms in paraplegic patients in the absence of a spinal gate because the brain is completely disconnected from the cord. Psychophysical specificity, in such a concept, makes no sense; instead we must explore how patterns of nerve impulses generated in the brain can give rise to somesthetic experience.

Phantom Limbs and the Concept of a Neuromatrix

But there is a set of observations on pain in paraplegic patients that just does not fit the theory. This does not negate the gate theory, of course. Peripheral and spinal processes are obviously an important part of pain and we need to know more about the mechanisms of peripheral inflammation, spinal modulation, midbrain descending control, and so forth. But the data on painful phantoms below the level of total spinal cord section18,19 indicate that we need to go above the spinal cord and into the brain.

The cortex, Gybels and Tasker made amply clear, is not the pain center and neither is the thalamus.20 The areas of the brain involved in pain experience and behavior must include somatosensory projections as well as the limbic system.

First, because the phantom limb feels so real, it is reasonable to conclude that the body we normally feel is subserved by the same neural processes in the brain as the phantom; these brain processes are normally activated and modulated by inputs from the body but they can act in the absence of any inputs.

Second, all the qualities of experience we normally feel from the body, including pain, are also felt in the absence of inputs from the body; from this we may conclude that the origins of the patterns of experience lie in neural networks in the brain; stimuli may trigger the patterns but do not produce them.

Third, the body is perceived as a unity and is identified as the ‘self’, distinct from other people and the surrounding world. The experience of a unity of such diverse feelings, including the self as the point of orientation in the surrounding environment, is produced by central neural processes and cannot derive from the peripheral nervous system or spinal cord.

Fourth, the brain processes that underlie the body-self are ‘built-in’ by genetic specification, although this built-in substrate must, of course, be modified by experience, including social learning and cultural influences. These conclusions provide the basis of the conceptual model18,19,21 depicted in Figure 3.

Figure 3. Factors that contribute to the patterns of activity generated by the body-self neuromatrix, which is comprised of sensory, affective, and cognitive neuromodules. The output patterns from the neuromatrix produce the multiple dimensions of pain experience, as well as concurrent homeostatic and behavioral responses.

Outline of the Theory

The anatomical substrate of the body-self is a large, widespread network of neurons that consists of loops between the thalamus and cortex as well as between the cortex and limbic system.18,19,21 The entire network, whose spatial distribution and synaptic links are initially determined genetically and are later sculpted by sensory inputs, is a neuromatrix. The loops diverge to permit parallel processing in different components of the neuromatrix and converge repeatedly to permit interactions between the output products of processing. The repeated cyclical processing and synthesis of nerve impulses through the neuromatrix imparts a characteristic pattern: the neurosignature. The neurosignature of the neuromatrix is imparted on all nerve impulse patterns that flow through it; the neurosignature is produced by the patterns of synaptic connections in the entire neuromatrix.

The neurosignature, which is a continuous output from the body-self neuromatrix, is projected to areas in the brain—the sentient neural hub—in which the stream of nerve impulses (the neurosignature modulated by ongoing inputs) is converted into a continually changing stream of awareness. Furthermore, the neurosignature patterns may also activate a second neuromatrix to produce movement, the action-neuromatrix .

The Body-Self Neuromatrix

The neuromatrix (not the stimulus, peripheral nerves or ‘brain center’) is the origin of the neurosignature; the neurosignature originates and takes form in the neuromatrix. Though the neurosignature may be activated or modulated by input, the input is only a ‘trigger’ and does not produce the neurosignature itself. The neuromatrix ‘casts’ its distinctive signature on all inputs (nerve impulse patterns) which flow through it.

The neuromatrix, distributed throughout many areas of the brain, comprises a widespread network of neurons which generates patterns, processes information that flows through it, and ultimately produces the pattern that is felt as a whole body.

Conceptual Reasons for a Neuromatrix

It is difficult to comprehend how individual bits of information from skin, joints, or muscles can all come together to produce the experience of a coherent, articulated body. At any instant in time, millions of nerve impulses arrive at the brain from all the body’s sensory systems, including the proprioceptive and vestibular systems. How can all this be integrated in a constantly changing unity of experience? Where does it all come together?

The neuromatrix, then, is a template of the whole, which provides the characteristic neural pattern for the whole body (the body’s neurosignature) as well as subsets of signature patterns (from neuromodules) that relate to events at (or in) different parts of the body

Alle har sett filmen The Matrix, sant? Spesielt scenen med «the spoonboy» er magisk: «Do not try to bend the spoon. That is impossible. Instead… only try to realize the truth» Neo: «What truth?». Spoonboy: «There is no spoon». Neo: «There is no spoon?». Spoonboy: «Then you´ll see, that it is not the spoon that bends, it is only your self». Dette har en direkte relasjon til smerteopplevelsen. Melzack forklarer:

Pain is not injury; the quality of pain experiences must not be confused with the physical event of breaking skin or bone. Warmth and cold are not ‘out there’; temperature changes occur ‘out there’, but the qualities of experience must be generated by structures in the brain. There are no external equivalents to stinging, smarting, tickling, itch; the qualities are produced by built-in neuromodules whose neurosignatures innately produce the qualities.

We do not learn to feel qualities of experience: our brains are built to produce them.

When all sensory systems are intact, inputs modulate the continuous neuromatrix output to produce the wide variety of experiences we feel. We may feel position, warmth, and several kinds of pain and pressure all at once. It is a single unitary feeling just as an orchestra produces a single unitary sound at any moment even though the sound comprises violins, cellos, horns, and so forth.

The experience of the body-self involves multiple dimensions—sensory, affective, evaluative, postural and many others.

To use a musical analogy once again, it is like the strings, tympani, woodwinds and brasses of a symphony orchestra which each comprise a part of the whole; each makes its unique contribution yet is an integral part of a single symphony which varies continually from beginning to end.

Action Patterns: The Action-Neuromatrix

The output of the body neuromatrix is directed at two systems: (1) the neuromatrix that produces awareness of the output, and (2) a neuromatrix involved in overt action patterns. Just as there is a steady stream of awareness, there is also a steady output of behavior (including movements during sleep).

It is important to recognize that behavior occurs only after the input has been at least partially synthesized and recognized. For example, when we respond to the experience of pain or itch, it is evident that the experience has been synthesized by the body-self neuromatrix (or relevant neuromodules) sufficiently for the neuromatrix to have imparted the neurosignature patterns that underlie the quality of experience, affect and meaning. Most behavior occurs only after inputs have been analyzed and synthesized sufficiently to produce meaningful experience.

When we reach for an apple, the visual input has clearly been synthesized by a neuromatrix so that it has 3-dimensional shape, color and meaning as an edible, desirable object, all of which are produced by the brain and are not in the object ‘out there’. When we respond to pain (by withdrawal or even by telephoning for an ambulance), we respond to an experience that has sensory qualities, affect and meaning as a dangerous (or potentially dangerous) event to the body.

After inputs from the body undergo transformation in the body-neuromatrix, the appropriate action patterns are activated concurrently (or nearly so) with the neuromatrix for experience. Thus, in the action-neuromatrix, cyclical processing and synthesis produces activation of several possible patterns, and their successive elimination, until one particular pattern emerges as the most appropriate for the circumstances at the moment. In this way, input and output are synthesized simultaneously, in parallel, not in series. This permits a smooth, continuous stream of action patterns.

Another entrenched assumption is that perception of one’s body results from sensory inputs that leave a memory in the brain; the total of these signals becomes the body image. But the existence of phantoms in people born without a limb or who have lost a limb at an early age suggests that the neural networks for perceiving the body and its parts are built into the brain.18,19,27,28

Phantoms become comprehensible once we recognize that the brain generates the experience of the body. Sensory inputs merely modulate that experience; they do not directly cause it.

Pain and Neuroplasticity

Plasticity related to pain represents persistent functional changes, or ‘somatic memories,’29–31 produced in the nervous system by injuries or other pathological events.

Denervation Hypersensitivity and Neuronal Hyperactivity

Clinical neurosurgery studies reveal a similar relationship between denervation and CNS hyperactivity. Neurons in the somatosensory thalamus of patients with neuropathic pain display high spontaneous firing rates, abnormal bursting activity, and evoked responses to stimulation of body areas that normally do not activate these neurons.34,35

Furthermore, in patients with neuropathic pain, electrical stimulation of subthalamic, thalamic and capsular regions may evoke pain36 and in some instances even reproduce the patient’s pain.37–39

It is possible that receptive field expansions and spontaneous activity generated in the CNS following peripheral nerve injury are, in part, mediated by alterations in normal inhibitory processes in the dorsal horn. Within four days of a peripheral nerve section there is a reduction in the dorsal root potential, and therefore, in the presynaptic inhibition it represents.40 Nerve section also induces a reduction in the inhibitory effect of A-fiber stimulation on activity in dorsal horn neurons.41

The fact that amputees are more likely to develop phantom limb pain if there is pain in the limb prior to amputation30 raises the possibility that the development of longer term neuropathic pain also can be prevented by reducing the potential for central sensitization at the time of amputation.52,53

Pain and Psychopathology

Pain that is ‘nonanatomical’ in distribution, spread of pain to non-injured territory, pain that is said to be out of proportion to the degree of injury, and pain in the absence of injury have all, at one time or another, been used as evidence to support the idea that psychological disturbance underlies the pain. Yet each of these features of supposed psychopathology can now be explained by neurophysiological mechanisms that involve an interplay between peripheral and central neural activity.4,60

This raises the intriguing possibility that the intensity of pain at the site of an injury may be facilitated by contralateral neurite loss induced by the ipsilateral injury68—a situation that most clinicians would never have imagined possible.

Taken together, these novel mechanisms that explain some of the most puzzling pain symptoms must keep us mindful that emotional distress and psychological disturbance in our patients are not at the root of the pain. In fact, more often than not, prolonged pain is the cause of distress, anxiety, and depression.

Attributing pain to a psychological disturbance is damaging to the patient and provider alike; it poisons the patient-provider relationship by introducing an element of mutual distrust and implicit (and at times, explicit) blame. It is devastating to the patient who feels at fault, disbelieved and alone.

Pain and Stress

We are so accustomed to considering pain as a purely sensory phenomenon that we have ignored the obvious fact that injury does not merely produce pain; it also disrupts the brain’s homeostatic regulation systems, thereby producing ‘stress’ and initiating complex programs to reinstate homeostasis. By recognizing the role of the stress system in pain processes, we discover that the scope of the puzzle of pain is vastly expanded and new pieces of the puzzle provide valuable clues in our quest to understand chronic pain.69

However, it is important for the purpose of understanding pain to keep in mind that stress involves a biological system that is activated by physical injury, infection, or any threat to biological homeostasis, as well as by psychological threat and insult of the body-self.

When injury occurs, sensory information rapidly alerts the brain and begins the complex sequence of events to re-establish homeostasis. Cytokines are released within seconds after injury. These substances, such as gamma-interferon, interleukins 1 and 6, and tumor necrosis factor, enter the bloodstream within 1–4 min and travel to the brain. The cytokines, therefore, are able to activate fibers that send messages to the brain and, concurrently, to breach the blood–brain barrier at specific sites and have an immediate effect on hypothalamic cells. The cytokines together with evaluative information from the brain rapidly begin a sequence of activities aimed at the release and utilization of glucose for necessary actions, such as removal of debris, the repair of tissues, and (sometimes) fever to destroy bacteria and other foreign substances. Following severe injury, the noradrenergic system is activated: epinephrine is released into the blood stream and the powerful locus coeruleus/norepinephrine system in the brainstem projects information upward throughout the brain and downward through the descending efferent sympathetic nervous system. Thus, the whole sympathetic system is activated to produce readiness of the heart, blood vessels, and other viscera for complex programs to reinstate homeostasis.70,71

At the same time, the perception of injury activates the hypothalamic–pituitary–adrenal (HPA) system and the release of cortisol from the adrenal cortex, which inevitably plays a powerful role in determining chronic pain. Cortisol also acts on the immune system and the endogeneous opioid system. Although these opioids are released within minutes, their initial function may be simply to inhibit or modulate the release of cortisol. Experiments with animals suggest that their analgesic effects may not appear until as long as 30 min after injury.

Cortisol is an essential hormone for survival because it is responsible for producing and maintaining high levels of glucose for rapid response after injury or major threat. However, cortisol is potentially a highly destructive substance because, to ensure a high level of glucose, it breaks down the protein in muscle and inhibits the ongoing replacement of calcium in bone. Sustained cortisol release, therefore, can produce myopathy, weakness, fatigue, and decalcification of bone. It can also accelerate neural degeneration of the hippocampus during aging. Furthermore, it suppresses the immune system.

Estrogen increases the release of peripheral cytokines, such as gamma-interferon, which in turn produce increased cortisol. This may explain why more females than males suffer from most kinds of chronic pain as well as painful autoimmune diseases such as multiple sclerosis and lupus.72

Some forms of chronic pain may occur as a result of the cumulative destructive effect of cortisol on muscle, bone, and neural tissue. Furthermore, loss of fibers in the hippocampus due to aging reduces a natural brake on cortisol release which is normally exerted by the hippocampus. As a result, cortisol is released in larger amounts, producing a greater loss of hippocampal fibers and a cascading deleterious effect

The cortisol output by itself may not be sufficient to cause any of these problems, but rather provides the conditions so that other contributing factors may, all together, produce them.

The fact that several autoimmune diseases are also classified as chronic pain syndromes—such as Crohn’s disease, multiple sclerosis, rheumatoid arthritis, scleroderma, and lupus—suggests that the study of these syndromes in relation to stress effects and chronic pain could be fruitful. Immune suppression, which involves prolonging the presence of dead tissue, invading bacteria, and viruses, could produce a greater output of cytokines, with a consequent increase in cortisol and its destructive effects.

In some instances, pain itself may serve as a traumatic stressor.

Phantom Limb Pain

The cramping pain, however, may be due to messages from the action-neuromodule to move muscles in order to produce movement. In the absence of the limbs, the messages to move the muscles become more frequent and ‘stronger’ in the attempt to move the limb. The end result of the output message may be felt as cramping muscle pain. Shooting pains may have a similar origin, in which action-neuromodules attempt to move the body and send out abnormal patterns that are felt as shooting pain. The origins of these pains, then, lie in the brain.

Low-Back Pain

Protruding discs, arthritis of vertebral joints, tumors, and fractures are known to cause low back pain. However, about 60–70% of patients who suffer severe low back pain show no evidence of disc disease, arthritis, or any other symptoms that can be considered the cause of the pain. Even when there are clear-cut physical and neurological signs of disc herniation (in which the disc pushes out of its space and presses against nerve roots), surgery produces complete relief of back pain and related sciatic pain in only about 60% of cases.

A high proportion of cases of chronic back pain may be due to more subtle causes. The perpetual stresses and strains on the vertebral column (at discs and adjacent structures called facet joints) produce an increase in small blood vessels and fibrous tissue in the area.78 As a result, there is a release of substances that are known to produce inflammation and pain into local tissues and the blood stream; this whole stress cascade may be triggered repeatedly. The effect of stress-produced substances—such as cortisol and norepinephrine—at sites of minor lesions and inflammation could, if it occurs often and is prolonged, activate a neuromatrix program that anticipates increasingly severe damage and attempts to counteract it.

Fibromyalgia

An understanding of fibromyalgia has eluded us because we have failed to recognize the role of stress mechanisms in addition to the obvious sensory manifestations which have dominated research and hypotheses about the nature of fibromyalgia. Melzack’s interpretation of the available evidence is that the body-self neuromatrix’s response to stressful events fails to turn off when the stressor diminishes, so that the neuromatrix maintains a continuous state of alertness to threat. It is possible that this readiness for action produces fatigue in muscles, comparable to the fatigue felt by paraplegics in their phantom legs when they spontaneously make cycling movements.24 It is also possible that the prolonged tension maintained in particular sets of muscles produces the characteristic pattern of tender spots.

The persistent low-level stress (i.e., the failure of the stress response to cease) would produce anomalous alpha waves during deep sleep, greater feelings of fatigue, higher generalized sensitivity to all sensory inputs, and a low-level, sustained output of the stress-regulation system, reflected in a depletion of circulating cortisol.

Skin Matters: Identifying Pain Mechanisms and Predicting Treatment Outcomes

juni 16, 2013 av Marius

Mye om huden relatert til smerte og nevropati! Mest relatert til biopsi, men mye kan knyttes til behandling også. Spesielt ved hemming av TRPV1.

http://www.hindawi.com/journals/nri/2013/329364/

This data has led to new insights into the potential pain mechanisms for various pain conditions including neuropathic pain (from small fiber neuropathies) and Complex Regional Pain Syndrome. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us. Cutaneous sensory neurons expressing nociceptive receptors such as transient receptor potential vanilloid 1 channels and voltage-gated sodium channels are critical for pain transmission. Epidermal cells (such as keratinocytes, Langerhans cells, and Merkel cells) express sensor proteins and neuropeptides; these regulate the neuroimmunocutaneous system and participate in nociception and neurogenic inflammation.

The skin has homeostatic and immunologic barrier functions, but acts as a complex sensory organ as well [1]. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us [2]. The neuroimmunocutaneous system (NICS) is responsible for the cutaneous sensations of touch, pressure, temperature, and pain. This sensory transduction occurs via primary afferent nerves following reciprocated signals between neuronal and nonneuronal skin cells of the NICS [1]. New data concerning peripheral pain mechanisms from within the skin have led to new insight into the potential pain mechanisms for various pain conditions including neuropathic pain syndromes such as diabetic neuropathy and Complex Regional Pain Syndrome.

In pain and neurogenic inflammation, TRPV1 is coexpressed on TRPA1-expressing sensory nerves; both integrate a variety of noxious stimuli [4]. Complex signaling pathways between cells of the NICS, such as keratinocytes, TRPV1-expressing nociceptors, and macrophages, lead to the release of neural growth factor (NGF), prostaglandins, opioids, proinflammatory cytokines, and chemokines [1]. These lead to sensitisation of the peripheral nerves by upregulating ionic channels and by inducing further spinal cord cytokine release [8].

2. Small Fiber Neuropathy (SFN)
Neuropathic pain arises as a direct consequence of a lesion or disease of the somatosensory system; it affects about 7% of the general population [10, 11].

Small fiber neuropathy is a neuropathy of the small nonmyelinated fibers and myelinated A delta fibers. Neuropathic pain occurs from small fiber neuropathy; small fiber neuropathy is caused by a wide variety of acquired and genetic disorders [12], many of which are treatable [13].

Diabetes mellitus is the most frequent underlying cause of SFN [14]. Other causes include toxic (e.g., alcohol), metabolic, immune-mediated, infectious, and hereditary causes.

About 60% of patients describe the painful sensation as spontaneous (burning, sunburn-like, paroxysmal, pruritic, and deep), with worsening at rest or during the night [12]; the sensation can be associated with thermal evoked pain (cold or warm) with or without allodynia, a painful response to a normally innocuous stimulus, and hyperalgesia, an increased response to a painful stimulus [12]. In addition there are negative sensory symptoms (thermal and pinprick hypoesthesia) that reflect peripheral deafferentation [19]. Sensation of cold feet is reported, though warm to touch. Thermal hypoesthesia with or without pinprick hypoesthesia has been detected in 40% of patients [20]; hyperalgesia and aftersensation have been detected in 10–20% of patients [12, 20].

2.3. Complex Regional Pain Syndrome (CRPS)

CRPS is a syndrome characterized by a continuing (spontaneous and/or evoked) regional pain, that is, seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion [23]. The pain is regional (not in a specific nerve territory or dermatome); it usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. It has signs of central sensitisation such as allodynia and hyperalgesia. The syndrome shows variable progression over time [23].

Accumulating experimental and clinical evidence supports the hypothesis that Complex Regional Pain Syndrome type I (CRPS-I) might indeed be a small fiber neuropathy [25]. Most post-traumatic inflammatory changes observed in CRPS are mediated by two peptides, CGRP and substance P [26]. The activation of cutaneous nociceptors can induce retrograde depolarisation of small-diameter primary afferents, causing release of neuropeptides such as substance P and CGRP from sensory terminals in the skin.

A specific diagnostic test for small fiber neuropathy is a skin biopsy; this includes a count of the intraepidermal small nerve fibers (IENF) that cross the basal membrane. The loss of IENF can be reliably measured and is currently used to diagnose small fiber neuropathy (SFN) [17].

Skin biopsy is much less invasive and more practical than peripheral nerve biopsy. It is a safe and reliable tool for investigating nociceptive fibers in human epidermis and dermis [29]. It can be performed at any site of the body, with a disposable punch, using a sterile technique, and under local anesthesia (Figure 2) [29].

A recent study assessed the usefulness of skin biopsy in the assessment of 145 patients with suspected SFN [21]. In 59% of patients skin biopsy was abnormal in at least one site [21]. Patients with confirmed SFN were significantly more likely to have pain; they were more than twice as likely to respond to standard neuropathic pain medications [21]. A positive response to neuropathic pain medications was seen in 84% of patients with an abnormal skin biopsy compared to only 42% of those with a normal biopsy [21]. Skin biopsy has a relatively high yield in patients with sensory symptoms with no findings of mixed fiber neuropathy on clinical examination or on nerve conduction studies [21].

Along with neuronal and immunological systems, the skin plays a critical role in sensory transduction [1]. Further direct targeting of the skin with topical agents should be considered. The interaction of TRPV1 and TRPA1 channels in the skin in painful conditions needs further exploration. Second generation TRPV1 antagonists (without on-target side effects of hyperthermia and burn risk) are under development [6].

In Pain Medicine, the skin does indeed matter!

Verkstedet Bodywork & Breathing System

Marius Blomsterviks nettside om forskning og kunnskap relatert til behandling av pust, ryggrad og smerte på Verkstedet Klinikk

Kategoriarkiv: Forskning og artikler

The gluten syndrome: A neurological disease

Intermittent Hypoxia Research in the Former Soviet Union and the Commonwealth of Independent States: History and Review of the Concept and Selected Applications

Response of skeletal muscle mitochondria to hypoxia

Two routes to functional adaptation: Tibetan and Andean high-altitude natives

Potential and Actual Points of Adaptation to Hypoxia

Energy Production.

Ventilation.

Oxygen in the Bloodstream.

Blood Flow and Oxygen Diffusion.

Differences in the control of breathing between Himalayan and sea-level residents

Effects of Slow Deep Breathing at High Altitude on Oxygen Saturation, Pulmonary and Systemic Hemodynamics

Physiological Sensing of Carbon Dioxide/Bicarbonate/pH via Cyclic Nucleotide Signaling

Fibromyalgia is not all in your head, new research confirms

Pain

Action Patterns: The Action-Neuromatrix

Skin Matters: Identifying Pain Mechanisms and Predicting Treatment Outcomes

2.3. Complex Regional Pain Syndrome (CRPS)