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Ten Steps to Understanding Manual and Movement Therapies for Pain

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Alt om smerte, kort fortalt, fra: http://www.somasimple.com/forums/showthread.php?t=4942
Nothing Simple – Ten Steps to Understanding Manual and Movement Therapies for Pain

1. Pain is a category of complex experiences, not a single sensation produced by a single stimulus.

2. Nociception (warning signals from body tissues) is neither necessary nor sufficient to produce pain. In other words, pain can occur in the absence of tissue damage.

3. A pain experience may be induced or amplified by both actual and potential threats.

4. A pain experience may involve a composite of sensory, motor, autonomic, endocrine, immune, cognitive, affective and behavioural components. Context and meaning are paramount in determining the eventual output response.

5. The brain maps peripheral and central neural processing into each of these components at multiple levels. Therapeutic input at a single level may be sufficient to resolve a threat response.

6. Manual and movement therapies may affect peripheral and central neural processes at various stages:
– transduction of nociception at peripheral sensory receptors
– transmission of nociception in the peripheral nervous system
– transmission of nociception in the central nervous system
– processing and modulation in the brain

7. Therapies that are most likely to be successful are those that address unhelpful cognitions and fear concerning the meaning of pain, introduce movement in a non-threatening internal and external context, and/or convince the brain that the threat has been resolved.

8. The corrective physiological mechanisms responsible for resolution are inherent. A therapist need only provide an appropriate environment for their expression.

9. Tissue length, form or symmetry are poor predictors of pain. The forces applied during common manual treatments for pain generally lack the necessary magnitude and specificity to achieve enduring changes in tissue length, form or symmetry. Where such mechanical effects are possible, the clinical relevance to pain is yet to be established. The predominant effects of manual therapy may be more plausibly regarded as the result of reflexive neurophysiological responses.

10. Conditioning for the purposes of fitness and function or to promote general circulation or exercise-induced analgesia can be performed concurrently but points 6 and 9 above should remain salient.

Bibliography

Books:
Pain: The Science of Suffering – Patrick Wall
The Challenge of Pain – Patrick Wall, Ronald Melzack
Explain Pain – David Butler, Lorimer Moseley
The Sensitive Nervous System – David Butler
Phantoms in the Brain – V. S. Ramachandran
Topical Issues in Pain Vol’s 1-5 – Louis Giffiord (ed)
The Feeling of What Happens – Antonio Damasio
Clinical Neurodynamics – Michael Shacklock
Eyal Lederman – The Science and Practice of Manual Therapy

Research articles:
Melzack R. Pain and the neuromatrix in the brain. J Dental Ed. 2001;65:1378-82.
Craig AD. Pain mechanisms: Labeled lines versus convergence in central processing. Ann Rev Neurosci. 2003;26:130.
Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev Neurosci. 2002;3:655-66.
Henderson LA, Gandevia SC, Macefield VG. Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: A single-trial fMRI study. Pain. 2007;128:20-30.
Olausson H, Lamarre Y, Backlund H, Morin C, Wallin BG, Starck G, Ekholm S, Strigo I, Worsley K, Vallbo AB, Bushnell MC. Unmyelinated tactile afferents signal touch and project to insular cortex. Nature Neurosci. 2002;5:900–904.
Moseley GL. A pain neuromatrix approach to patients with chronic pain. Manual Ther. 2003;8:130-40.
Moseley GL. Unravelling the barriers to reconceptualisation of the problem in chronic pain: The actual and perceived ability of patients and health professionals to understand the neurophysiology. J Pain. 2003;4:184-89.
Moseley GL, Arntz A. The context of a noxious stimulus affects the pain it evokes. Pain. 2007;133(1-3):64-71.
Moseley, GL, Nicholas, MK and Hodges, PW. A randomized controlled trial of intensive neurophysiology education in chronic low back pain. Clin J Pain. 2004;20:324-30.
Crombez G, Vlaeyen JWS, Heuts PH et al. Pain-related fear is more disabling than pain itself. Evidence on the role of pain-related fear in chronic back pain disability. Pain. 1999;80:329-40.
Zusman M. Forebrain-mediated sensitization of central pain pathways: ‘non-specific’ pain and a new image for manual therapy. Manual Ther. 2002;7:80-88.
Dorko B. The analgesia of movement: Ideomotor activity and manual care. J Osteopathic Med. 2003;6:93-95.
Threlkeld AJ. The effects of manual therapy on connective tissue. Phys Ther. 1992;72:893-902.
Lederman E. The myth of core stability. Retrieved at: http://www.ppaonline.co.uk/

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THE VALUE OF BLOWING UP A BALLOON

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Dette er en veldig viktig artikkel for å forstå diafragmas rolle i både pust og bevegelse, og ifh smertetilstander i ryggraden. Nevner en lovende teknikk for å styrke diafragma og støttemuskulatur hvor man blåser opp en ballong og strammer kjernemuskulaturen. Nevner Zone of Apposition (ZOA) som beskriver diafragmas bevegelsesmuligheter. Ved lav ZOA har diafrgma lite bevegelse. Vi ønsker å øke ZOA. Denne øvelsen er konstruert basert på fysioterapeutisk prinsipper, men i Verkstedet Breathing System har vi øvelser som er gir samme resultater på diafragma, men bygget på lang og erfaringsbasert tradisjon fra tibetansk buddhisme.

Nevner også hvordan mage-pust minker bevegelsen i diafragma.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2971640/

Suboptimal breathing patterns and impairments of posture and trunk stability are often associated with musculoskeletal complaints such as low back pain. A therapeutic exercise that promotes optimal posture (diaphragm and lumbar spine position), and neuromuscular control of the deep abdominals, diaphragm, and pelvic floor (lumbar-pelvic stabilization) is desirable for utilization with patients who demonstrate suboptimal respiration and posture. This clinical suggestion presents a therapeutic exercise called the 90/90 bridge with ball and balloon. This exercise was designed to optimize breathing and enhance both posture and stability in order to improve function and/or decrease pain. Research and theory related to the technique are also discussed.

Many muscles used for postural control/stabilization and for respiration are the same, for example: the diaphragm, transversus abdominis, and muscles comprising the pelvic floor.1–6 Maintaining optimal posture/stability and respiration is important and is even more challenging during exercise. Exercise increases respiratory demand (e.g. running) and limb movements (e.g. arms moving while standing still) increase postural demands for stabilization.3,7

Many factors are potentially involved with suboptimal respiration and suboptimal (faulty) posture and may be associated with musculoskeletal complaints such as low back pain, and/or sacroiliac joint pain.8 (Table 1)

Suboptimal Respiration and Posture
Decreased/suboptimal Zone of Apposition of diaphragm
Decreased exercise tolerance
Decreased intra-abdominal pressure
Shortness of Breath/Dyspnea
Decreased respiratory efficiency
Decreased expansion of lower rib cage/chest
Decreased appositional diaphragm force
Decreased length of diaphragm (short)
Decreased transdiaphragm pressure
Increased use of accessory muscles of respiration
Poor neuromuscular control of core muscles
Increased lumbar lordosis
Increased anterior pelvic tilt
Increased hamstring length
Increased abdominal length
Rib elevation/external rotation
Sternum elevation
Increased activity of paraspinals
Increased lumbar-pelvic instability
Low back pain
Sacroiliac Joint pain
Thoracic Outlet Syndrome
Headaches
Asthma

One of the most critical factors, often overlooked by physical therapists, is maintaining an optimal zone of apposition of the diaphragm.3,9–11 The zone of apposition (ZOA) is the area of the diaphragm encompassing the cylindrical portion (the part of the muscle shaped like a dome/umbrella) which corresponds to the portion directly apposed to the inner aspect of the lower rib cage.12 The ZOA is important because it is controlled by the abdominal muscles and directs diaphragmatic tension. When the ZOA is decreased or suboptimal, there are several potential negative consequences. (Table 1) Two examples include:

  1. Inefficient respiration (less air in and out) because the transdiaphragmatic pressure is reduced.11 The smaller the ZOA, there will be less inspiratory action of the diaphragm on the rib cage.11
  2. Diminished activation of the transversus abdominis which is important for both respiration and lumbar stabilization.11,13

The incidence of LBP has been documented to be as high as 30% in the athletic population, and in many cases pain may persist for years.15 Low back pain is frequently correlated with faulty posture such as an excessive lumbar lordosis.16–18 Excessive lumbar lordosis may be associated with over lengthened and weak abdominal musculature.18–20 Poor neuromuscular control of core muscles (transversus abdominis, internal oblique, pelvic floor and diaphragm) has been described in individuals with SIJ pain21 and in individuals with lumbar segmental instability, potentially adversely affecting respiration.22

Richardson et al.27 describe coordination of the Transversus abdominis and the diaphragm in respiration during tasks in which stability is maintained by tonic activity of these muscles. During inspiration, the diaphragm contracts concentrically, whereas the transversus abdominis contracts eccentrically. The muscles function in reverse during exhalation with the diaphragm contracting eccentrically while the transversus abdominis contracts concentrically. Hodges et al. noted that during respiratory disease the coordinating function between the transversus abdominis and diaphragm was reduced.6 Thus, it is also possible that faulty posture such as over lengthened abdominals and excessive lordosis could reduce the coordination of the diaphragm and transversus abdominis during respiration and stabilization activities.

O’sullivan et al.21 studied subjects with LBP attributed to the sacroiliac joints and compared them to control subjects without pain. O’sullivan et al. compared respiratory rate and diaphragm and pelvic floor movement using real time ultrasound during a task that required load transfer through the lumbo-pelvic region (the active straight leg raise test). Subjects with pain had an increase in respiratory rate, descent of their pelvic floor and a decrease in diaphragm excursion as compared to the control subjects, who had normal respiratory rates, less pelvic floor descent, and optimal diaphragm excursion. While O’sullivan et al. concluded that an intervention program focused on integrating control of deep abdominal muscles with normal pelvic floor and diaphragm function may be effective in managing patients with LBP,21 they did not describe strategies or exercises to achieve this goal.21

While the role of the Transversus abdominis in lumbar stability is well documented, less well known is the role of the diaphragm in lumbar stability. While the primary function of the diaphragm is respiration, it also plays a role in spinal stability.3,28

The right hemidiaphragm attaches distally to the anterior portions of the first through third lumbar vertebrae (L1-3) and the left hemidiaphragm attaches distally on the first and second lumbar vertebrae (L1-2).29 This section of the diaphragm is referred to as the crura. Of interest is the asymmetrical attachment of the diaphragm with the left hemidiaphragm attaching to L1-2 and the right portion attaching to L1-3.

During the inhalation phase of ventilation, the dome of the diaphragm moves caudally like a piston creating a negative pressure in the thorax that forces air into the lungs. This action is normally accompanied by a rotation of the ribs outward (external rotation) largely in part due to the ZOA.12 (Figure 1) Apposition is a term that means multiple layers adjacent to each other.33 The normal force of pull on the sternal and costal portions of the diaphragm would produce an internal rotation of the ribs. The ZOA creates an external rotation of these ribs primarily because the pressure in the thoracic cavity prevents an inward motion. The crural portion of the diaphragm assists the caudal motion of the dome. It also pulls the anterior lumbar spine upward (cephalad and anterior). Additionally, the abdominal muscles and pelvic floor musculature are less active to allow visceral displacement due to the dome of the diaphragm dropping. With exhalation, this process is reversed. Abdominal muscle activity compresses the viscera in the abdominal cavity, the diaphragm is forced cephalad and the ribs internally rotate. As exhalation becomes forced as during exercise, abdominal activity (rectus abdominus, internal obliques, external obliques, and transversus abdominis) will be increased.34–36

When the ZOA is optimized, the respiratory and postural roles of the diaphragm have maximal efficiency.37 In suboptimal positions (i.e. decreased ZOA), the diaphragm has a decreased ability to draw air into the thorax because of less caudal movement upon contraction and less effective tangential tension of the diaphragm on the ribs and therefore lower transdiaphragmatic pressure.38 This decreased ZOA is accompanied by decreased expansion of the rib cage, postural alterations, and a compensatory increase in abdominal expansion.12 (Figure 2)

One such adaptive breathing strategy would be to relax the abdominal musculature more than necessary on inspiration to allow for thoraco-abdominal expansion. This situation leads to decreased abdominal responsibility while breathing and can contribute to instability. This would reflect more upper chest breathing and less efficient diaphragm activity. If the body maintains this position and breathing strategy for an extended period of time, the diaphragm may adaptively shorten and the lungs may become hyperinflated.37,39,40 Hyperinflation may also contribute to over use of accessory muscles of respiration such as scalenes, sternocleidomastoid (SCM), pectorals, upper trapezius and paraspinals in an attempt to expand the upper rib cage.41–44 Again, without an optimal dome shape/position of the diaphragm or an optimal ZOA the body compensates to get air in with accessory muscles since the more linear/flat/short diaphragm is less efficient for breathing.32

Instructions for Performance of the 90/90 Bridge with Ball and Balloon: 1. Lie on your back with your feet flat on a wall and knees and hips bent at a 90-degree angle. 2. Place a 4-6 inch ball between your knees. 3. Place your right arm above your head and a balloon in your left hand. 4. Inhale through your nose and as you exhale through your mouth, perform a pelvic tilt so that your tailbone is raised slightly off the mat. Keep low back flat on the mat. Do not press your feet into the wall, instead pull down with your heels. 5. You should feel the back of your thighs and inner thighs engage, keeping pressure on the ball. Maintain this position for the remainder of the exercise. 6. Now inhale through your nose and slowly blow out into the balloon. 7. Pause three seconds with your tongue positioned on the roof of your mouth to prevent airflow out of the balloon. 8. Without pinching the neck of the balloon and keeping your tongue on the roof of your mouth, inhale again through your nose. 9. Slowly blow out as you stabilize the balloon with your left hand. 10. Do not strain your neck or cheeks as you blow. 11. After the fourth breath in, pinch the balloon neck and remove it from your mouth. Let the air out of the balloon.12. Relax and repeat the sequence 4 more times. Copyright © Postural Restoration Institute™ 2009, used with permission

The patient/athlete is asked to hold the balloon with one hand and inhale through his/her nose with the tongue on the roof of the mouth (normal rest position) and then exhale through his/her mouth into the balloon. The inhalation, to about 75% of maximum, is typically 3-4 seconds in duration, and the complete exhalation is usually 5-8 seconds long followed by a 2-3 second pause. This slowed breathing is thought to further relax the neuromuscular system/parasympathetic nervous system and generally decrease resting muscle tone. Ideally the patient/athlete will be able to inhale again without pinching off the balloon with their teeth, lips, or fingertips. This requires maintenance of intra-abdominal pressure to allow inhalation through the nose without the air coming back out of the balloon and into the mouth.

When the exercise is performed by the patient/athlete with hamstring and gluteus maximus (glut max) activation (hip extensors) the pelvis moves into a relative posterior pelvic tilt and the ribs into relative depression and internal rotation. This pelvic and rib position helps to optimize abdominal length (decreases) and diaphragm length/ZOA (increases).

Clinical experience with the BBE includes utilization of the exercise for both female and male patients (more females than males), ages 5-89 with a wide variety of diagnoses including: low back pain, trochanteric bursitis, SIJ pain, asthma, COPD, acetabular labral tear, anterior knee pain, thoracic outlet syndrome (TOS) and sciatica.

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Brain Mechanisms Supporting the Modulation of Pain by Mindfulness Meditation

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En studie som gir en tydelig beskrivelse av hvor mye mindfulness demper smerte. De fant ingen korrelasjon mellom pustefrekvens og smertereduksjon, men det kan være flere faktorer som spiller inn der.  I denne studien gjorde de f.eks. kun 20 min meditasjon i 4 dager, med mennesker som ikke har meditert først. De andre studiene inkluderer mennesker som har meditert lenge. I tillegg kan man tydelig se at etter 4 dager med meditasjon så blir pustefrekvensen lavere når man blir påført vond varme, noe som tyder på at de begynner å bruke pusten som smertereduksjon. Det var motsatt før de hadde fått instruksjon i meditasjon.

http://www.jneurosci.org/content/31/14/5540.full

After 4 d of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57% and pain intensity ratings by 40% when compared to rest.

Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas. Together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.

Mindfulness-based mental training.

Mindfulness-based mental training was performed in four separate, 20 min sessions conducted by a facilitator with >10 years of experience leading similar meditation regimens. Subjects had no previous meditative experience and were informed that such training was secular and taught as the cognitive practice of Shamatha or mindfulness meditation. Each training session was held with one to three participants.

On mindfulness meditation training day 1, subjects were encouraged to sit with a straight posture, eyes closed, and to focus on the changing sensations of the breath occurring at the tips of their nostrils. Instructions emphasized acknowledging discursive thoughts and feelings and to return their attention back to the breath sensation without judgment or emotional reaction whenever such discursive events occurred. On training day 2, participants continued to focus on breath-related nostril sensations and were instructed to “follow the breath,” by mentally noting the rise and fall of the chest and abdomen. The last 10 min were held in silence so subjects could develop their meditative practice. On training day 3, the same basic principles of the previous sessions were reiterated. However, an audio recording of MRI scanner sounds was introduced during the last 10 min of meditation to familiarize subjects with the sounds of the scanner. On the final training session (day 4), subjects received minimal meditation instruction but were required to lie in the supine position and meditate with the audio recording of the MRI sounds to simulate the scanner environment. Contrary to traditional mindfulness-based training programs, subjects were not required to practice outside of training.

Subjects also completed the Freiburg Mindfulness Inventory short-form (FMI), a 14-item assessment that measures levels of mindfulness, before psychophysical pain training and after MRI session 2. The FMI is a psychometrically validated instrument with high internal consistency (Cronbach α = 0.86) (Walach et al., 2006). Statements such as “I am open to the experience of the present moment” are rated on a five-point scale from 1 (rarely) to 5 (always). Higher scores indicate more skill with the mindfulness technique.

Decreases in respiration rate have been reported previously to predict reductions in pain ratings (Grant and Rainville, 2009; Zautra et al., 2010). In the present data (MRI session 2; n = 14), no significant relationship between the decreased respiration rates and pain intensity (p = 0.22, r = −0.35), pain unpleasantness (p = 0.41, r = −0.24), or FMI ratings (p = 0.42, r = 0.24) was found.

CBF Respiration rate Heart rate
Session 1
    Rest: neutral 74.12 (3.01) 19.97 (1.29) 72.53 (2.33)
    Rest: heat 71.51 (2.93) 20.45 (1.11) 74.79 (2.39)
    ATB: neutral 70.69 (3.56) 17.05 (1.00) 70.46 (1.79)
    ATB: heat 67.90 (3.08) 19.32 (1.33) 74.07 (2.19)
Session 2
    Rest: neutral 68.57 (3.17) 16.72 (0.82) 74.82 (3.08)
    Rest: heat 66.82 (2.59) 17.12 (0.93) 77.32 (2.95)
    Meditation: neutral 65.09 (3.59) 11.55 (0.74) 73.62 (2.77)
    Meditation: heat 65.47 (3.86) 9.47 (0.67)a 75.38 (2.70)

In the present investigation, meditation reduced all subjects’ pain intensity and unpleasantness ratings with decreases ranging from 11 to 70% and from 20 to 93%, respectively.

Meditation likely modulates pain through several mechanisms. First, brain areas not directly related to meditation exhibited altered responses to noxious thermal stimuli. Notably, meditation significantly reduced pain-related afferent processing in SI (Fig. 5), a region long associated with sensory-discriminative processing of nociceptive information (Coghill et al., 1999). Executive-level brain regions (ACC, AI, OFC) are thought to influence SI activity via anatomical pathways traversing the SII, insular, and posterior parietal cortex (Mufson and Mesulam, 1982; Friedman et al., 1986;Vogt and Pandya, 1987). However, because meditation-induced changes in SI were not specifically correlated with reductions in either pain intensity or unpleasantness, this remote tuning may take place at a processing level before the differentiation of nociceptive information into subjective sensory experience.

Second, the magnitude of decreased pain intensity ratings was associated with ACC and right AI activation (Fig. 6). Activation in the mid-cingulate and AI overlapped between meditation and pain, indicating a likely substrate for pain modulation. Converging lines of evidence suggest that these regions play a major role in the evaluation of pain intensity and fine-tuning afferent processing in a context-relevant manner (Koyama et al., 2005; Oshiro et al., 2009;Starr et al., 2009). Such roles are consistent with the aspect of mindfulness meditation that involves reducing appraisals that normally impart significance to salient sensory events.

Third, OFC activation was associated with decreases in pain unpleasantness ratings (Fig. 6). The OFC has been implicated in regulating affective responses by manipulating the contextual evaluation of sensory events (Rolls and Grabenhorst, 2008) and processing reward value in the cognitive modulation of pain (Petrovic and Ingvar, 2002). Meditation directly improves mood (Zeidan et al., 2010a), and positive mood induction reduces pain ratings (Villemure and Bushnell, 2009). Therefore, meditation-related OFC activation may reflect altered executive-level reappraisals to consciously process reward and hedonic experiences (e.g., immediate pain relief, positive mood) (O’Doherty et al., 2001; Baliki et al., 2010; Peters and Büchel, 2010).

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The Polyvagal Perspective

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Denen Studien beskriver Stephen Porges sitt arbeid med å forstå Vagus nerven og hvordan den forholder seg til pusten og til psyken.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868418/

The Polyvagal Theory introduced a new perspective relating autonomic function to behavior that included an appreciation of autonomic nervous system as a “system,” the identification of neural circuits involved in the regulation of autonomic state, and an interpretation of autonomic reactivity as adaptive within the context of the phylogeny of the vertebrate autonomic nervous system. The paper has two objectives: First, to provide an explicit statement of the theory; and second, to introduce the features of a polyvagal perspective. The polyvagal perspective emphasizes how an understanding of neurophysiological mechanisms and phylogenetic shifts in neural regulation, leads to different questions, paradigms, explanations, and conclusions regarding autonomic function in biobehavioral processes than peripheral models. Foremost, the polyvagal perspective emphasizes the importance of phylogenetic changes in the neural structures regulating the autonomic nervous system and how these phylogenetic shifts provide insights into the adaptive function and the neural regulation of the two vagal systems

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Carbon dioxide and the critically ill—too little of a good thing?

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Omfattende studie av alle de gode egenskapene ved hyperkapni – høyt CO2 nivå. Nevner mange interessante ting, bl.a. at CO2 indusert acidose gir mye mindre fire radikaler enn om pH senkes av andre faktorer. Bekrefter også at oksygen blir sittende fast på blodcellene ved hypokapni, og at melkesyreproduksjonen begrensens når acidosen er pga CO2 men ikke når den er av andre faktorer.

Spesielt med denne artikkelen er at den beskriver forskjellene på en hyperkapni acidose og acidose av andre faktorer. Hyperkapnisk acidose har beskyttende egenskaper.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02388-0/fulltext

Permissive hypercapnia (acceptance of raised concentrations of carbon dioxide in mechanically ventilated patients) may be associated with increased survival as a result of less ventilator-associated lung injury.
Accumulating clinical and basic scientific evidence points to an active role for carbon dioxide in organ injury, in which raised concentrations of carbon dioxide are protective, and low concentrations are injurious.
Although hypercapnic acidosis may indicate tissue dysoxia and predict adverse outcome, it is not necessarily harmful per se. In fact, it may be beneficial. There is increasing evidence that respiratory (and metabolic) acidosis can exert protective effects on tissue injury, and furthermore, that hypocapnia may be deleterious.
If hypoventilation is allowed in an effort to limit lung stretch, carbon dioxide tension increases. Such “permissive hypercapnia” may be associated with increased survival in acute respiratory distress syndrome (ARDS);2 this association is supported by outcome data from a 10-year study.3
Furthermore, hypocapnia shifts the oxyhaemoglobin dissociation curve leftwards, restricting oxygen off-loading at the tissue level; local oxygen delivery may be further impaired by hypocapnia-induced vasoconstriction.
Brain homogenates develop far fewer free radicals and less lipid peroxidation when pH is lowered by carbon dioxide than when it is lowered by hydrochloric acid.19
Finally, greater inhibition of tissue lactate production occurs when lowered pH is due to carbon dioxide than when it is due to hydrochloric acid.20
An association between hypoventilation, hypercapnia, and improved outcome has been established in human beings.2, 5, 21 In lambs, ischaemic myocardium recovers better in the presence of hypercapnic acidosis than metabolic acidosis.22 Hypercapnic acidosis has also been shown to protect ferret hearts against ischaemia,23 rat brain against ischaemic stroke,16 and rabbit lung against ischaemia-reperfusion injury.24 Hypercapnia attenuates oxygen-induced retinal vascularisation,25 and improves retinal cellular oxygenation in rats.26 “pH-stat” management of blood gases during cardiopulmonary bypass, involving administration of large amounts of additional carbon dioxide for maintenance of temperature-corrected PaCO2, results in better neurological and cardiac outcome.27
Hypercapnia results in a complex interaction between altered cardiac output, hypoxic pulmonary vasoconstriction, and intrapulmonary shunt, with a net increase in PaO2 (figure).28 Because hypercapnia increases cardiac output, oxygen delivery is increased throughout the body.28 Regional, including mesenteric, blood flow is also increased,29 thereby increasing oxygen delivery to organs. Because hypercapnia (and acidosis) shifts the haemoglobin-oxygen dissociation curve rightwards, and may increase packed-cell volume,30 oxygen delivery to tissues is further increased. Acidosis may reduce cellular respiration and oxygen consumption,31 which may further benefit an imbalance between supply and demand, in addition to greater oxygen delivery. One hypothesis32 is that acidosis protects against continued production of further organic acids (by a negative feedback loop) in tissues, providing a mechanism of cellular metabolic shutdown at times of nutrient shortage—eg, ischaemia.
Acidosis attenuates the following inflammatory processes (figure): leucocyte superoxide formation,33 neuronal apoptosis,34phospholipase A2 activity,35 expression of cell adhesion molecules,36 and neutrophil Na+/H+ exchange.37 In addition, xanthine oxidase (which has a key role in reperfusion injury) is inhibited by hypercapnic acidosis.24 Furthermore, hypercapnia upregulates pulmonary nitric oxide38 and neuronal cyclic nucleotide production,39 both of which are protective in organ injury. Oxygen-derived free radicals are central to the pathogenesis of many types of acute lung injury, and in tissue homogenates, hypercapnia attenuates production of free radicals and decreases lipid peroxidation.19 Thus, during inflammatory responses, hypercapnia or acidosis may tilt the balance towards cell salvage at the tissue level.
However, we know from several case series that human beings, and animals, can tolerate exceptionally high concentrations of carbon dioxide, and when adequately ventilated, can recover rapidly and completely. Therefore, high concentrations (if tolerated) may not necessarily cause harm.
From the published studies reviewed, and from the pathological mechanisms assessed, we postulate that changes in carbon dioxide concentration might affect acute inflammation,33—36 tissue ischaemia,16 ischaemia-reperfusion,20, 24 and other metabolic,12, 21,32 or developmental14 processes.
We argue that the recent shift in thinking about hypercapnia must now be extended to therapeutic use of carbon dioxide. Our understanding of the biology of disorders in which hypocapnia is a cardinal element would require fundamental reappraisal if hypocapnia is shown to be independently harmful.
In summary, in critically ill patients, future therapeutic goals involving PaCO2 might be expressed as:“keep the PaCO2 high; if necessary, make it high; and above all, prevent it from being low”.
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Effects of a 4-week training with voluntary hypoventilation carried out at low pulmonary volumes

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Spennende studie som viser hvordan lav pustefrekvens i selve trening påvirker restitusjonen etterpå. F.eks. hvordan bikarbonat/natron (HCO3-) påvirker melkesyreterskel. Teknikken bestod i å holde pusten 4 sekunder etter utpust, i bolker a 5minutter i løpet av treningsperioden. Det gir spesielt lite oksygen i blodet, som gir mange positive resultater.

http://www.sciencedirect.com/science/article/pii/S1569904807002327

Helle studien her:  http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CCsQFjAA&url=http%3A%2F%2Fwww.researchgate.net%2Fpublication%2F5689789_Effects_of_a_4-week_training_with_voluntary_hypoventilation_carried_out_at_low_pulmonary_volumes%2Ffile%2F79e41509ccd387b0f9.pdf&ei=pM58UpS3IIKF4ATU24D4CA&usg=AFQjCNFVh6Yl8e_ScphKf6HTFiLp1CWKsw&sig2=B9Zq9u_LuDDzGru14OKsLQ&bvm=bv.56146854,d.bGE

This study investigated the effects of training with voluntary hypoventilation (VH) at low pulmonary volumes. Two groups of moderately trained runners, one using hypoventilation (HYPO, n = 7) and one control group (CONT, n = 8), were constituted. The training consisted in performing 12 sessions of 55 min within 4 weeks. In each session, HYPO ran 24 min at 70% of maximal O2 consumption (View the MathML source) with a breath holding at functional residual capacity whereas CONT breathed normally. A View the MathML source and a time to exhaustion test (TE) were performed before (PRE) and after (POST) the training period. There was no change in View the MathML source, lactate threshold or TE in both groups at POST vs. PRE. At maximal exercise, blood lactate concentration was lower in CONT after the training period and remained unchanged in HYPO. At 90% of maximal heart rate, in HYPO only, both pH (7.36 ± 0.04 vs. 7.33 ± 0.06; p < 0.05) and bicarbonate concentration (20.4 ± 2.9 mmol L−1 vs. 19.4 ± 3.5; p < 0.05) were higher at POST vs. PRE. The results of this study demonstrate that VH training did not improve endurance performance but could modify the glycolytic metabolism. The reduced exercise-induced blood acidosis in HYPO could be due to an improvement in muscle buffer capacity. This phenomenon may have a significant positive impact on anaerobic performance.

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Respiratory Dysregulation in Anxiety, Functional Cardiac, and Pain Disorders

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Svært mye interessant i denne studien om pusten og CO2. Spesielt avsnittene om at kronisk smerte endrer pustemønsteret og senker CO2 nivået i kroppen.

http://www.ncbi.nlm.nih.gov/pubmed/11530714

http://www.mental-mechanics.org/pdf/Anxiety/FH%20Wilhelm%20et%20al%20-%20Respiratory%20dysregulation%20review.pdf

CHRONIC PAIN
Acute pain results in shortness of breath and an increase in ventila- tion (Nishino, Shimoyama, Ide, & Isono, 1999). A commonly used pain provocation in the laboratory is immersion of a limb into almost freezing water (cold pressor test), which is reliably followed by reduc- tions of PetCO2 among healthy people. (On the other hand, partial or full immersion of the face in cold water causes a modest reduction in ventilation, a component of the diving response). Patients who experi- ence intense chronic pain show these respiratory-related changes over extended periods. For example, migraine headache patients were found to have significantly lowered PetCO2 levels during an attack compared to controls and to migraine-free periods (Hannerz & Jogestrand, 1995), and there were even respiratory abnormalities immediately before an attack (Zhao, Sand, & Sjaastad, 1992). Glynn, Lloyd, & Folkhard (1981) examined arterial pH and PCO2 in 52 chronic pain patients (e.g., back pain, cancer-related pain). PCO2 was mark- edly lowered in these patients, and nerve blockade of pain resulted in a significant rise in PCO2.

Interestingly, blood pH was normal, indicat- ing a long-term blood chemistry compensation for chronic hyperven- tilation. In a sleep study of fibromyalgia patients, a high incidence of respiratory abnormalities such as periodic breathing were found, and arterial PCO2 was lowered in a subgroup of patients (Sergi et al., 1999). Many clinicians, including one of the present authors (Gevirtz), have had the opportunity to measure PetCO2 levels in hun- dreds of chronic muscle pain patients, and the clinical impression is that these levels are almost universally low (c.f., Timmons & Ley, 1994). Of course, pain may also play a role in the increased ventilation found in the FCD patients discussed above, especially during acute episodes of chest pain.

The increased ventilation during acute pain is likely a component of the fight-flight response, preparing the individual for immediate action and sometimes for being attacked or maybe injured. Interest- ingly, recent evidence from animal studies indicates that acute hyperventilation has anesthetic effects via the adrenergic and endogenous opiate system (Ide et al., 1994a, 1994b). Thus, the increased ventila- tion that first served to activate an individual for a fight may have the beneficial side effect of relieving pain if the fight is lost.

So far, no study we know of has examined if the chronic hyperventi- lation exhibited by pain patients is of any benefit to their pain experi- ence (and thus a coping strategy), is only a side effect of the intense pain, or makes their pain worse. One would expect that chronic hyper- ventilation is not healthy in these patients, as it is in other clinical groups, because it interferes with blood homeostatic mechanisms and can lead to a variety of physical symptoms. It has been suggested that by numbing pain, hyperventilation may become a short-term adaptive process with long-term negative consequences (Conway, 1994). Inter- esting in this context is that opioids are frequently prescribed to chronic pain patients to suppress their pain, and they typically also suppress ventilation via central nervous pathways, sometimes to a lethal extent. In summary, there is some initial evidence that hyper- ventilation plays a role in chronic pain, and some mediating mecha- nisms have been identified. However, most of the pain-hypocapnia relationship in chronic pain syndromes is not well understood.

Chronic Pain
Slow abdominal breathing is often taught as a relaxation technique in preparation for acute pain, such as surgery or childbirth, and it also helps patients counteract their tendency to hyperventilate during such events. As described above, the chronic hyperventilation that can accompany long-lasting pain may be especially problematic because it may have long-term negative organismic effects. It is therefore logi- cal that breathing training could be a valuable asset in the overall treat- ment of chronic pain disorders. However, no data are currently avail- able on the role of breathing training as a systematic intervention in these disorders. It is one author’s (Gevirtz) clinical experience that breathing training is in fact a powerful tool in a comprehensive pain management protocol. This is also a common assumption of most bodywork therapies of pain (c.f., Clifton-Smith, 1998). Here again, the capnometry readings are used to illustrate the physiological basis of the symptomatology.

Muscular pain can result from chronically tense muscles. Hubbard, Gevirtz, and their colleagues recently showed that a sympathetically mediated pathway to muscle spindles (trigger points), rather than pathways to muscle fibers, plays an important role in the maintenance of chronic muscular pain (Gerwin, Shannon, Hong, Hubbard, & Gevirtz, 1997; Hubbard & Berkoff, 1993; McNulty, Gevirtz, Hub- bard, & Berkoff, 1994). Psychological stress increased the activity of these spindles, which suggests that stress reduction could alleviate chronic muscle pain. Thus, relaxation induced by slow diaphragmatic breathing may have a beneficial effect on the activation of these spin- dles and reduce general muscle tension.

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Muscle Pain: Mechanisms and Clinical Significance

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En studie til fra Siegfried Mense, om muskelsmerter. Han har ikke fått med seg at trykksensitive nerver kun finnes i huden. Og han har misforstått litt i forskjellene mellom hud-smerter og muskel-smerter siden han sier at hud-smerter ikke kan ha utstrålende effekt. Han har tydeligvis ikke ikke inkludert subcutane nerver i sin vurdering.

Men mye interessant i denne studien likevel. Spesielt vektleggingen av at lav pH er den viktigste bidragsyteren til muskelsmerter.

Han nevner at input fra muskel-nociceptorer har større relevans i ryggmargen enn input fra huden. Derfor er betennelser og lav pH de viktigste drivkreftene i kroniske smerter.

Nevner også at smerter henger sammen, f.eks. at trapezius kan stramme seg for å beskytte brachialis, slik at smerten kjennes i trapezius, mens problemet egentlig sitter i brachialis.

Beskriver også triggerpunkter, men sier at det foreløpig er veldig mange ubesvarte spørsmål om denne teorien.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696782

Muscle pain is a major medical problem: in, the majority (60% to 85%) of the population has had (nonspecific) back pain of muscular origin at some time or other (lifetime prevalence) (1). Pain evoked by myofascial trigger points has a point prevalence of approximately 30% (2). More than 7% of all women aged 70 to 80 years suffer from the fibromyalgia syndrome (e1). In an Italian study, musculoskeletal pain was found to be the most common reason that patients consulted a doctor (3). Thus, treating physicians should be aware of the mechanisms of muscle pain, insofar as they are currently understood.

Subjective differences between muscle pain and cutaneous pain

Muscle pain Cutaneous pain
Electrical nerve stimulation induces only one pain Electrical nerve stimulation induces a first pain and a second pain
Poorly localizable Well-localized
Tearing, cramping, pressing quality Stabbing, burning, cutting quality
Marked tendency toward referral of pain No tendency toward referral of pain
Affective aspect: difficult to tolerate Affective aspect: easier to tolerate

Muscle pain is produced by the activation of specific receptors (so-called nociceptors): these receptors are specialized for the detection of stimuli that are objectively capable of damaging tissue and that are subjectively perceived as painful. They consist of free nerve endings and are connected to the central nervous system (CNS) by way of unmyelinated (group IV) or thinly myelinated (group III) fibers. They can be sensitized and activated by strong mechanical stimuli, such as trauma or mechanical overloading, as well as by endogenous inflammatory mediators including bradykinin (BK), serotonin, and prostaglandin E2 (PGE2).

Two activating chemical substances are particularly important for the generation of muscle pain: adenosine triphosphate (ATP) and protons (H+ ions).

ATP activates muscle nociceptors mainly by binding to the P2X3 receptor molecule, H+ mainly by binding to the receptor molecules TRPV1 (transient receptor potential vanilloid 1) and ASICs (acid-sensing ion channels) (4).

ATP is found in all cells of the body and is released whenever bodily tissues of any type are injured.

A drop in pH is probably one of the main activators of peripheral nociceptors, as many painful disturbances of muscle are associated with low pH in muscle tissue.

Nerve growth factor (NGF) also has a connection to muscle pain: NGF is synthesized in muscle and activates muscle nociceptors (e2). NGF synthesis is increased when a muscle is inflamed (e3).

Acidic tissue pH is one of the main activating factors leading to muscle pain. Practically all pathological and pathophysiological changes of skeletal muscle are accompanied by a drop in pH, among them

  • chronic ischemic states,
  • tonic contractions or spasms,
  • myofascial trigger points,
  • (occupationally induced) postural abnormalities, and
  • myositides.

The neuropeptides stored in muscle nociceptors are released not only when peripheral stimuli activate the nerve endings, but also when spinal nerves are compressed. In this type of neuropathic pain, action potentials are generated at the site of compression and spread not only centripetally, i.e., toward the central nervous system, but also centrifugally, i.e., toward the nociceptive endings, where they induce the release of vasoactive neuropeptides. In this way, neurogenic inflammation comes about, characterized by hyperemia, edema, and the release of inflammatory mediators (8). The inflammatory mediators sensitize the muscle nociceptors and thereby increase neuropathic pain.

The sensitization of the muscle nociceptors by endogenous mediators such as BK and PGE2 is one of the reasons why patients with muscle lesions suffer from tenderness to pressure on the muscle, and from pain on movement or exercise. It is also the reason why many types of muscle pain respond well to the administration of non-steroidal anti-inflammatory drugs (NSAID), which block prostaglandin synthesis.

An influx of nervous impulses from muscle nociceptors into the spinal cord increases the excitability of posterior horn neurons to a greater extent than one from cutaneous nociceptors (9).

Two main mechanisms underlie the overexcitability of spinal nociceptive neurons:

A structural change of ion channels, rendering them more permeable to Na+ and Ca2+, is the short-term result of an influx of nociceptive impulses into the spinal cord. Among other effects, this causes originally ineffective («silent» or «dormant») synapses to become effective.

A change of gene transcription in the neuronal nucleus, leading to a modification of synthetic processes, causes new ion channels to be synthesized and incorporated into the nerve cell membrane. The long-term result of central sensitization is a nociceptive cell whose membrane contains a higher density of ion channels that are also more permeable to ions. This explains the hyperexcitability of the cell. Glial cells, too, particularly microglia, can contribute to the sensitization of central neurons by secreting substances such as tumor necrosis factor a (TNF-a) (8).

The increased excitability of spinal neurons and the spread of excitation within the CNS are the first steps in the process of chronification of muscle pain. The endpoint of chronification consists of structural remodeling processes in the CNS that open up new pathways for nociceptive information and cause pain to persist over the long term. Patients with chronic muscle pain are difficult to treat, because the functional and structural changes in the CNS need time to regress. The fact that not all muscle pain becomes chronic implies that chronification requires not only the mechanisms just discussed, but also other ones, e.g., a genetic predisposition.

Pain arising in muscle is more likely to be referred pain than pain arising in the skin. Referred pain is pain that is felt not (only) at its site of origin, but at another site some distance away. A possible mechanism of referred pain is the spread, within the spinal cord, of excitation due to the muscle lesion (9) (figures 2 and ​and3).3). As soon as the excitation reaches sensory posterior horn neurons that innervate an area beyond the site of the original muscle lesion, the patient feels referred pain in that area, even though none of the nociceptors in it are activated (13).


An example is shown in figure 3: a stimulus delivered to the myofascial trigger point (MTrP) in the soleus muscle causes only mild local pain, while the patient feels more severe (referred) pain in the sacroiliac joint. No conclusive answers are yet available to the questions of why muscle pain is more likely than cutaneous pain to be referred, why it is usually not referred to both proximal and distal sites, and why pain referral is often discontinuous. There is, however, a well-known discontinuity of spinal topography between the C4 and T2 dermatomes.

The main reason why pain arises in muscle spasm is muscle ischemia, which leads to a drop in pH and the release of pain-producing substances such as bradykinin, ATP, and H+.

The vicious-circle concept of muscle spasm – muscle pain causes spasm, which causes more pain, etc. – should now be considered obsolete. Most studies have shown that muscle pain lowers the excitability of the α-motor neurons innervating the painful muscle (14) (a «pain adaptation» model) (15).

Muscle spasm can be precipitated by, among other things, pain in another muscle. Thus, a spasm-like increase EMG activity in the trapezius muscle has been described in response to painful stimulation of the biceps brachii muscle (16). Another source of muscle spasms is pathological changes in a neighboring joint. These sources of pain must be deliberately sought.

In a widespread hypothesis on the origin of MTrP’s (19), it is supposed that a muscular lesion damages the neuromuscular endplate so that it secretes an excessive amount of acetylcholine. The ensuing depolarization of the muscle cell membrane produces a contraction knot that compresses the neighboring capillaries, causing local ischemia. Ischemia, in turn, leads to the release of substances into the tissue that sensitize nociceptors, accounting for the tenderness of MTrP’s to pressure. Substances of this type have been found to be present within the MTrP’s of these patients (20). This supposed mechanism leaves many questions unanswered but is currently the only comprehensive hypothesis on the origin of MTrP’s.

Patients with MTrP’s often have pain in three locations:

  • at the site of the MTrP itself,
  • at the origin or insertion of the affected muscle, because of pulling by the muscle fibers that have been stretched by the contraction knots,
  • and referred pain outside the MTrP (figure 3).

Because the MTrP is cut off from its blood supply by compression of the local microcirculation, oral NSAID’s are not very effective against TrP pain.

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Functional Anatomy of Muscle – Muscle, Nociceptors and Afferent Fibers

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Svært mye interessant om nervesystemets rolle i muskler og smerte.

Spesielt at det er ingen frie nerveender i muskelcellene, men bare i blodkarene i musklene. Derfor reagerer vi med smerte på betennelser og lav pH i blodet, mens trykksensitiviteten kun sitter i huden.

Den nevner at pH sensibiliteten er den viktigste smertebidraget fordi pH synker i de fleste patologiske tilstander, f.eks. hard trening eller skade.

Den nevner at det er mer SP (Substans P, som er relatert til smerte) i huden enn i muskler.

Nevner at frie nerveender ikke går til kapillærer eller muskelceller, bare til arterioler og venuler.

Nevner også innervering av bindevev, og at dette feltet foreløpig er lite studert og oversett. Spesielt viser de til at Toracolumbar Facia (i korsryggen) har størst innervasjon av C-fiber nociceptorer(som inneholder SP) under huden, og litt i multifidene.

En nociceptor er ikke bare en passiv mottaker av impulser, men er også en aktiv deltaker i vevets tilstand når det gjelder betennelser og blodsirkulasjon for de sender nevropetider ut fra doresalhornet til vevet (antidromiske impulser). Altså motsatt vei av reseptor-signalretningen.

CGRP virker vasodilerende, mens SP gjør at blodkarveggenes permeabilitet øker. Når permeabiliteten øker siver det ut proteiner og stoffer som egentlig ikke skal være i vevet, og da økes betennelser og immunsystemets aktivitet. Så det er SP vi ønsker å dempe først og fremst.

http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&ved=0CCsQFjAA&url=http%3A%2F%2Fwww.springer.com%2Fcda%2Fcontent%2Fdocument%2Fcda_downloaddocument%2F9783540850205-c1.pdf%3FSGWID%3D0-0-45-935848-p173845615&ei=_GJEUqyUOevn4QSBl4HQDg&usg=AFQjCNEpyWrolHywvUNyw_Cwa8yWTiEUnw&sig2=OJLZ3XrnTalCUUqE-uhCeQ&bvm=bv.53217764,d.bGE

The predominant location of free nerve endings supplied by group IV fibers was the adventitia of arterioles and venules. Surprisingly, muscle fibers themselves did not receive direct innervation by free nerve endings. Group III afferents generated not only free nerve endings but also paciniform corpuscles, whereas group IV fibers terminated exclusively in free nerve endings.The high sensitivity of the free nerve endings to chemical stimuli, particularly to those accompanying inflammatory lesions or disturbances of the microcirculation, may be related to their location on or in the walls of the blood vessels. The finding that the muscle fibers proper are not supplied by free nerve endings (Reinert et al. 1998) may relate to the clinical experience that muscle cell death is usually not painful, at least not if it occurs slowly, as for instance during muscular dystrophy, polymyositis, or dermatomyositis. A different situation is tearing of a muscle fiber bundle, which can be extremely painful. In this condi- tion, many muscle cells are destroyed simultaneously and release their contents (e.g., K+ ions and ATP) in the interstitial space, from where they can diffuse to the next nociceptive endings.
In skeletal muscle, the free nerve endings appear to be distributed quite evenly in the proximodistal direction. At least, in a quantitative evaluation of the inner- vation density by neuropeptide-(SP- and CGRP-) containing fibers, no difference between the proximal and distal portions of the rat gastrocnemius–soleus (GS) muscle was found (Reinert et al. 1998). Therefore, a higher innervation density at the transition zone between muscle and tendon is not a probable explanation for the frequent pain in this region.

However, in the same study the nerve fiber density in the peritendineum (the connective tissue around a tendon) of the rat calcaneal tendon was found to be several times higher than that in the GS muscle. In contrast, the collagen fiber bundles of the tendon tissue proper were almost free of free nerve endings. The high fiber density in the peritendineum may explain the high prevalence of tenderness or pain in the tissue around the tendon and the insertion site. The scarcity of nerve endings in the center of the tendon may relate to the clinical observation that (incomplete) ruptures of the tendon may occur without pain.

Judging from their respon- siveness to pain-producing agents, the following receptor molecules are likely to be relevant for muscle pain and tenderness (Mense and Meyer 1985; Caterina and David 1999; McCleskey and Gold 1999; Mense 2007):

  • Bradykinin (BKN) receptors (B1 and B2). BKN is cleaved from blood plasma proteins when a blood vessel breaks or increases its permeability so that plasma proteins enter the interstitial space. In intact tissue, BKN excites nerve endings by the activation of the BKN receptor molecule B2, whereas under pathological conditions (e.g., inflammation) the receptor B1 is the predominant one (Perkins and Kelly 1993; for a review of receptor molecules mediating the effects of classic inflammatory (pain-producing or algesic) substances, see Kumazawa 1996).
  • Serotonin receptors (particularly 5-HT3). Serotonin (5-hydroxytryptamin, 5-HT) is released from blood platelets during blood clotting. The stimulating effects of serotonin on nociceptive terminals in the body periphery are predomi- nantly mediated by the 5-HT3 receptor (at present, more than 15 different 5-HT receptors are known in the CNS). The serotonin concentrations released in the tissue are usually not sufficient to excite nociceptors directly, but they can sen- sitize them, i.e., make them more sensitive to other pain-producing agents such as BKN.
  • Prostaglandins, particularly prostaglandin E2 (PGE2). Prostaglandins (PGs) are released in a pathologically altered muscle by the enzymatic action of cycloox- igenases. PGE2 binds to a G protein-coupled prostanoid receptor (EP2) in the membrane of the nociceptive ending. Similarly to serotonin, PGE2 sensitizes nociceptors rather than exciting them under (patho)physiological circumstances (Mense 1981).
  • Acid-sensing ion channels (ASICs). ASICs constitute a family of receptor molecules that are sensitive to a drop in pH and open at various pH values. The channel proteins react already to small pH changes, for instance from pH 7.4 to 7.1. This receptor family (for instance ASIC1 and ASIC3) is particularly impor- tant for muscle pain, because almost all pathologic changes in muscle are accom- panied by a drop in tissue pH, e.g., exhausting exercise, ischemia, and inflammation (Immke and McCleskey 2003). In these conditions, the pH of the muscle tissue can drop to 5–6. The proton-sensitive nociceptors may also be of importance for the induction of chronic muscle pain. Repeated intramuscular injections of acidic solutions have been reported to induce a long-lasting hyper- algesia (Sluka et al. 2001).
  • P2X3 receptors. This receptor is a subtype of the purinergic receptors that are activated by ATP and its derivatives (Burnstock 2007; Ding et al. 2000). ATP is the energy-carrying molecule in all cells of the body; accordingly, it is present in every tissue cell. It is released from all tissues during trauma and other pathologic changes that are associated with cell death. For this reason, ATP has been considered a general signal substance for tissue trauma and pain (Cook and McCleskey 2002). ATP is particularly important for muscle pain, because it is present in muscle cells in high concentration (Stewart et al. 1994). When injected into human muscle, ATP causes pain (Mo ̈rk et al. 2003).
  • Transient receptor potential receptor subtype 1 (TRPV1) formerly called VR1. This receptor is one of the most important molecules for the induction of pain. The natural stimulant for the TRPV1 receptor is Capsaicin, the active ingredient of chilli peppers (Caterina and Julius 2001). The receptor is also sensitive to an increase in H+-concentration and to heat, with a threshold of approximately 39C. Its endoge- nous ligands are H+-ions.
  • Other TRP receptors. TRPV4 is a mechanosensitive ion channel that is sensitive to both weak and strong (noxious) intensities of local pressure (Liedtke 2005). It may be the receptor for mediating pain evoked by pinching and squeezing.
  • Tyrosine kinase A (TrkA) receptor. The ligand of this receptor is NGF (Caterina and David 1999). NGF is well-known for its sensitizing action on nociceptors in the body periphery and neurons in the CNS; it is synthesized in muscle, and its synthesis is increased during pathophysiological changes of the muscle (e.g., inflammation, Menetrey et al. 2000; Pezet and McMahon 2006).
  • Glutamate receptors. There is evidence indicating that the NMDA receptor (one of the receptors for glutamate) is present on nociceptive endings in masticatory muscles. Injections of glutamate into the masseter muscle in human subjects induced a reduction in pressure pain threshold which was attenuated by coinjection with ketamine, an NMDA receptor antagonist (Cairns et al. 2006).
Substances exciting muscle nociceptors independent of membrane receptors.
  • Hypertonic saline: injections of NaCl solutions (4.5–6.0%) have long been and still are used to elicit pain from deep somatic tissues (Kellgren 1938; for review, see Graven-Nielsen 2006).
  • Potassium ions: The most likely explanation for the excitatory action of high concentrations of extracellular potassium ions is a depolarization of the membrane potential due to a reduction of the inside–outside potassium gradient (usually the potassium concentration inside the axon is much higher).

DRG cells projecting in a cutaneous nerve have been reported to contain SP, CGRP, and somatostatin (SOM).

In comparison to skin nerves, muscle nerves appear to contain less SP. This finding makes sense, because the vasodilatation and plasma extrava- sation caused by the release of SP and CGRP from free nerve endings (see below) would be dangerous for skeletal muscles, since many of them are surrounded by a tight fascia. Therefore, an SP-induced muscle edema would result in a high increase in interstitial pressure, and could cause muscle necrosis.

In a study on functionally identified DRG cells employing a combination of electrophysiological and immunohistochemical techniques, Lawson et al.(1997) reported that cells terminating in cutaneous nociceptive endings showed a strong tendency to express SP, particularly if they had a slow conduction velocity or a small soma in the DRG. 

The peptides are synthesized in the somas of the DRG or in ganglion cells of cranial nerves. They are transported to both the central and the peripheral terminal of the primary afferent unit.

In a quantitative evaluation of neuropeptide-containing free nerve endings and preterminal axons (both characterized by varicosities) in the GS muscle of the rat, most endings were found around small blood vessels (arterioles or venules), whereas capillaries and the muscle cells proper were not contacted by these end- ings.

Efferent or motor fibers conduct action potentials from the CNS to the periphery; their soma is located in the spinal cord or brainstem and the fibers leave the CNS via the ventral root or cranial nerve motor roots. An exception are postganglionic sympathetic fibers whose cell bodies are mostly located in the sympathetic trunk (e.g., vasomotor fibers that constrict blood vessels).

The nerve to a locomotor muscle in the cat (the lateral GS) is composed of approximately one-third myelinated (720) and two-thirds unmyelinated (2,480) fibers (Table 2.2; Mitchell and Schmidt 1983; Stacey 1969). Nearly one quarter of the myelinated (group III) fibers had nociceptive properties in neurophysio- logical experiments (Mense and Meyer 1985). Of the unmyelinated fibers, 50% are sensory (group IV), and of these, approximately 55% have been found to be nociceptive in the rat (Hoheisel et al. 2005).

Data obtained from one muscle nerve cannot be transferred directly to other muscle nerves, because considerable differences exist between different muscles. For instance, neck muscle nerves of the cat contain unusually high numbers of sensory group III receptors (Abrahams et al. 1984). One possible explanation for these differences is that the muscles have different functions and environmental conditions: in contrast to the neck muscles, which must register the orientation of the head in relation to the body in fine detail, the locomotor hindlimb muscles often have to contract with maximal strength and under ischemic conditions.

In addition to nociceptors, there are other muscle receptors whose function is essential for the understanding of muscle pain:

  • Muscle spindles are complex receptive structures that consist of several specialized muscle fibers (the so-called intrafusal muscle fibers; the name is derived from their location inside the spindle-shaped connective tissue sheath. Accordingly, all the “normal” muscle fibers outside the spindle are “extrafusal” fibers). Muscle spindles measure the length and the rate of length changes of the muscle, i.e., their discharge rate increases with increasing muscle length and with increasing velocity of the length change.
  • Golgi (tendon) organs measure the tension of the muscle. They are arranged in series with the extrafusal muscle fibers; their location is the transition zone between muscle and tendon. The supplying fiber is the Ib afferent, whose structure is identical to the Ia fiber (thick myelin sheath and high conduction velocity). The receptor has a much simpler structure than the muscle spindle; it consists of receptive endings that are interwoven between the collagen fiber bundles of the tendon.
  • Muscle spindles and Golgi organs are proprioceptors, i.e., they measure the internal state of the body.
  • Pacinian corpuscles (PC) and paciniform corpuscles. These receptors do not respond to static pressure; they require dynamically changing mechanical stimuli, and are best excited by vibrations of relatively high frequency (close to 300 Hz; Kandel et al. 2000). The receptive ending is formed like a rod, and covered by several concentric membranes which give the receptor an onion-like appearance in cross-sections.

At present, little information is available about the innervation of fascia. This is an important gap in our knowledge, because fascia is an important component of the musculoskeletal system and likely to contribute to many forms of pain that are subsumed under the label “muscle” pain. One example is low back pain: The thoracolumbar fascia (TF) plays an essential role in body posture and trunk move- ments (Bogduk and Macintosh 1984). It is not only a passive transmitter of mechanical forces of the low back and abdominal muscles but also contractile by itself (Schleip et al. 2005).

In the connective tissue around the superficial lamina of the TF we found many CGRP- and SP-containing free nerve endings. The majority of the fibers were located in the subcutaneous layer, as well as between the fascia and the surface of the multifidus muscle (Fig. 2.8). The SP-positive endings are of particular interest, because they are thought to be nociceptors.
The loose connective tissue around the TF is probably deformed during any trunk movement, and therefore the free nerve endings are strategically situated to sense any disorders in these movements. It is conceivable that overload of the fascia puts mechanical stress and irritation on the endings, and thus may contribute to low back pain.
SP then releases histamine from mast cells, and together with CGRP these agents cause vasodilatation and an increase in vascular permeability of the blood vessels around the active ending. The result is a shift of blood plasma from the intravascular to the interstitial space. Outside the blood vessel, BKN is cleaved from the plasma protein kallidin, serotonin (5-HT) is set free from platelets, and PGs (particularly PGE2) from endothelial and other tissue cells. All these substances sensitize nociceptors. Thus, the main tissue alteration induced by a nondestructive noxious mechanical stimulus is a localized region of vasodilatation, edema, and sensitized nociceptors.
A nociceptor is not a passive sensor of tissue-threatening stimuli; it actively influences the microcirculation and chemical composition of the intersti- tial space around it.
If a noxious stimulus activates only one part of the ending, the action potentials originating in that region of the ending can invade antidromically (against the normal direction of propagation) those branches of the ending that were not excited by the stimulus. These antidromic action potentials release neuropeptides from the unstimulated branches. The whole process is called the axon reflex.  It is assumed to be the reason for the visible wheal and flare around a cutaneous lesion.

The vascular permeability is increased mainly by SP (and by the neurokinins A and B; Gamse and Saria 1985), whereas CGRP is assumed to act primarily as a vasodilator. There is evidence showing that CGRP enhances the plasma extravasation induced by SP and neurokinins A and B, but reduces the vasodilatory action of SP by desensitizing muscle arterioles to the peptide (O ̈ hle ́n et al. 1988).

The area of wheal and flare after a localized damage to the skin – for instance around a needle prick – could be an indicator of the extent of the excited nocicep- tive ending.

The size of the receptive fields (RFs) of cutaneous polymodal nociceptors was found to be less than 2 mm in cat (Bessou and Perl 1969) and 6–32 mm in rabbit (Kenins 1988). A receptive field is that region of the body from which a receptive ending (or a central sensory neuron) can be excited. The above figures are larger than the reported length of the branches of a nociceptor ending (a few hundred mm; Stacey 1969).

The release of SP, CGRP, neurokinin A, and other agents from nociceptors is the central factor in the cascade of events that lead to neurogenic inflammation in the periphery (Lembeck and Holzer 1979). Neurogenic inflammation is characterized by tissue edema and infiltration by immune cells, i.e., it exhibits the major histo- logical signs of a (sterile) inflammation. It develops whenever action potentials are generated not at the receptive ending but somewhere along the course of primary afferent units (spinal nerve or dorsal root). The action potentials propagate both to the CNS (causing pain) and to the peripheral ending (causing release of neuropep- tides and neurogenic inflammation). The published data indicate that vasodilatation can be elicited by antidromic stimulation of both Ad- and C fibers, but increase in vascular permeability and plasma extravasation by stimulation of C fibers only.

Neuropathies and radiculopathies and other pathological conditions that are asso- ciated with antidromic activity in sensory nerve fibers are examples of such events (Marchand et al. 2005). Neurogenic inflammation is likely to increase the dysesthe- sia and pain of patients suffering from neuropathies.

Inflammatory disorders are usually accompanied by sensitization of peri- pheral nociceptors, which is one source of inflammatory pain (for details, see Chap. 3). 

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NF-κB Links CO2 Sens ing to Innate Immuni ty and Inflammation in Mammalian Cells

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Viktig studie som nevner at økt CO2 kan dempe betennelser.

http://www.jimmunol.org/content/185/7/4439.long

In this study, we demonstrate that mammalian cells (mouse embryonic fibroblasts and others) also sense changes in local CO2 levels, leading to altered gene expression via the NF-κB pathway. IKKα, a central regulatory component of NF-κB, rapidly and reversibly translocates to the nucleus in response to elevated CO2. This response is independent of hypoxia-inducible factor hydroxylases, extracellular and intracellular pH, and pathways that mediate acute CO2-sensing in nematodes and flies and leads to attenuation of bacterial LPS-induced gene expression. These results suggest the existence of a molecular CO2 sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation.

FIGURE 7.Hypercapnia promotes an anti-inflammatory profile of gene expression. A PCR array of genes known to be involved in the NF-κB signaling cascade was performed on A549 cells exposed to ambient or 10% CO2 ± LT (100 ng/ml) for 4 h. A selection of differentially expressed genes from the array were chosen for validation. CCL2 (A), ICAM1 (B), TNF-α (C), and IL-10 (D) message levels were determined by quantitative real-time PCR and expressed as a percentage of LT-induced gene expression at 0.03% CO2 (n = 3 ± SEM, one-way ANOVA, Tukey post-test).

Traditionally, CO2 has been considered a waste product of respiration, and its biologic activity is poorly understood in terms of gene expression. However, a recent study reported differential gene expression in elevated CO2 (9).

This study suggests the existence of an intracellular CO2 sensor that is associated with anti-inflammatory and immunosuppressive signaling, is independent of intracellular and extracellular pH, and could account for the above clinical observations. CO2 can profoundly influence the transcriptional activation of the NF-κB pathway but its transcriptional effects may extend to other as yet uncharacterized pathways. Understanding the molecular mechanisms of CO2-dependent intracellular signaling could lead to new therapies in which the suppression of immunity or inflammation is clinically desirable.