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Allodynia mediated by C-tactile afferents in human hairy skin

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Viktig studie med alt om hudens c-fibre og deres relasjon til smerte (allodynia). Nevner at det er en samling av flere mekanoreseptorer i både muskel og hud som gir opphav smerte, ikke enkeltvis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180003/ 

We show that gentle tactile stimulation (vibration and brushing) of the hairy skin can exacerbate the underlying muscle pain (allodynia) evoked by infusion of hypertonic saline into the tibialis anterior muscle. This effect is dependent upon a low-threshold, mechanosensitive class of nerve fibres in the hairy skin known as C-tactile (CT) fibres. Knowledge of the role of CT fibres in allodynia increases our understanding of the mechanisms that underlie sensory-perceptual abnormalities – a common manifestation of clinical-pain states and neurological disorders.

We recently showed a contribution of low-threshold cutaneous mechanoreceptors to vibration-evoked changes in the perception of muscle pain. Neutral-touch stimulation (vibration) of the hairy skin during underlying muscle pain evoked an overall increase in pain intensity, i.e. allodynia. This effect appeared to be dependent upon cutaneous afferents, as allodynia was abolished by intradermal anaesthesia.
 Sustained muscle pain was induced by infusing hypertonic saline (HS: 5%) into tibialis anterior muscle (TA). Sinusoidal vibration (200 Hz–200 μm) was applied to the hairy skin overlying TA. Pain ratings were recorded using a visual analogue scale (VAS).
During tonic muscle pain (VAS 4–6), vibration evoked a significant and reproducible increase in muscle pain (allodynia) that persisted following compression of myelinated afferents. During compression block, the sense of vibration was abolished, but the vibration-evoked allodynia persisted.  In contrast, selective anaesthesia of unmyelinated cutaneous afferents abolished the allodynia, whereas the percept of vibration remained unaffected.
It is widely accepted that discriminative touch is mediated exclusively by large-diameter sensory fibres, whereas painful sensations are mediated by small-diameter fibres. Consistent with this view, selective microstimulation of a single large-diameter myelinated afferent in awake human subjects evokes a fundamental, innocuous (non-painful) sensation that has the quality of pressure, flutter or vibration according to the type of primary afferent excited (Ochoa & Torebjork, 1983; Vallbo et al. 1984; Macefield et al. 1990).
In addition to cutaneous nociceptors, which have high mechanical thresholds, there is another class of unmyelinated (C) fibre that has low mechanical thresholds. The existence of low-threshold unmyelinated afferents, termed C-mechanoreceptors, which respond to light touch of the skin, was documented long ago in the hairy skin of the cat and monkey (Zotterman, 1939; Maruhashi et al. 1952; Douglas & Ritchie, 1957; Bessou et al. 1971). Although some investigators had suggested that C low-threshold mechanoreceptors (CLTMs) are vestigial (Kumazawa & Perl, 1977), recent studies have reported a class of unmyelinated fibres in the human hairy skin, known as C-tactile (CT) fibres, that responds to innocuous mechanical stimulation (Johansson et al. 1988; Nordin, 1990; Vallbo et al.1993).
The response properties of CT fibres have been described using a limited range of stimuli – most notably slowly moving, low-force, mechanical stimuli such as finger stroking and soft brushing (Nordin, 1990; Vallbo et al. 1993, 1999; Lokenet al. 2009).
 It is this latter observation, together with the results of neuroimaging studies that have demonstrated that CT-mediated inputs project onto the insular cortex, which has underpinned the proposition of a CT-mediated emotional touch system (Olausson et al. 2002; Cole et al. 2006;McGlone et al. 2007; Olausson et al. 2008).  Intriguingly, in healthy subjects gentle brushing – known to elicit CT fibre responses – can evoke a neutral or even unpleasant sensation at the lowest brushing velocities (Loken et al. 2009), suggesting that gentle tactile stimulation can elicit opposing aspects of touch, i.e. predilection and aversion. A contribution of CT fibres to unpleasant touch has been suggested by recent work showing the activation of superficial dorsal horn neurons by gentle brushing of skin (Andrew, 2010; Craig, 2010). Similarly, these fibres have been implicated in touch hypersensitivity after injury in mice (Seal et al. 2009).
In a recent pilot study we found that innocuous tactile stimulation (vibration) of hairy skin intensified the underlying muscle pain (allodynia), and that this effect appeared to be dependent upon cutaneous mechanoreceptors as the allodynia was abolished by intradermal anaesthesia (Nagi et al. 2009).
The ambiguity in the literature about the contribution of different fibre classes to allodynia may be attributed in part to the use of a single-compartment model in which innocuous and noxious stimuli are applied to the same or adjacent regions of skin. Such an approach can lead to uncertainty as to whether any change in pain perception reflects peripheral sensitization of nociceptive fibres and/or an altered central convergence of innocuous and noxious inputs.
The muscle is physically separated from the skin by sheet-like fascia and each is supplied by separate vascular and nerve supplies (O’Rahilly & Muller, 1986; Berry et al. 1995;Salmons, 1995; Gibson et al. 2009). Within the hairy skin it is known that such low-amplitude vibratory stimuli are preferentially encoded by hair follicle afferents at low frequencies (~5 Hz to 100 Hz) and by Pacinian corpuscle receptors at high frequencies (~50 Hz to 1000 Hz: Merzenich & Harrington, 1969; Mahns et al. 2006). Although the response properties of CT fibres to vibratory stimulation remain untested, low-threshold mechanical sensitivity has been demonstrated using soft brushing (Vallbo et al. 1999; Olausson et al. 2002;Loken et al. 2009).
We have shown that innocuous cutaneous vibration can increase the intensity of underlying muscle pain, induced by intramuscular infusion of hypertonic saline, and that this effect (i) persists during compression blockade of myelinated fibres but (ii) is abolished by selective anaesthesia of unmyelinated cutaneous afferents. Thus, vibration-evoked allodynia is evidently dependent upon intact C fibre inputs from the skin, and that these C-fibres have a low mechanical threshold (they responded to 200 μm vibration).
Vibration was described as non-painful by all subjects prior to the induction, and following cessation, of muscle pain. Our observations clearly implicate the mechanically sensitive C-tactile (CT) fibres in mediating this vibration-evoked allodynia. In contrast to earlier work, our psychophysical data indicate that the mechanical sensitivity of CT fibres need not be limited to slowly moving stimuli, as allodynia was evoked by vibration following blockade of myelinated afferents.
Using the same data presented by Loken et al.(2009) an alternative explanation can be advanced, namely that C-fibre and large-diameter afferents are activated in parallel during brush stroking, with a sense of pleasantness emerging when large-diameter responsiveness exceeds that of C-fibres.
In our study, brushing stimulation – at reportedly pleasant speeds – evoked allodynia during muscle pain. Thus, it is the concurrent activation of muscle nociceptors during hypertonic saline infusion and cutaneous mechanoreceptors during brushing (and vibratory) stimulation that leads to the allodynia.
In our study, brushing stimulation – at reportedly pleasant speeds – evoked allodynia during muscle pain. Thus, it is the concurrent activation of muscle nociceptors during hypertonic saline infusion and cutaneous mechanoreceptors during brushing (and vibratory) stimulation that leads to the allodynia. The use of differential nerve blocks to avoid the co-activation of multiple fibre classes during tactile stimulation – an ambiguity that has plagued earlier studies – confirms the role of CT fibres in mediating allodynia. Hence, it is the complement of active sensory fibres, rather than the activation of a single class of afferents, which determines the perceptual outcome of activating CT fibres. 
 
Neuroimaging studies have shown differential representation of pleasant and painful tactile stimuli in certain areas of the brain involved in emotional processing (insular, orbitofrontal and anterior cingulate cortices: Olausson et al. 2002; Rolls et al. 2003). However, cortical activation evoked by a neutral tactile stimulus predominantly activates the discriminative-cognitive areas, the primary and secondary somatosensory cortices.
The qualia of touch may have evolved mainly in a social context to create a useful construct of the world, e.g. to predict whether the intent behind another’s action was benign or sinister; synthesized with the sense of ‘self’, these inputs subserve reflective self-awareness that characterizes humans as immensely social creatures (Ramachandran, 2004).
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C-tactile fibers contribute to cutaneous allodynia after eccentric exercise.

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Mer om huden og c-fibre i relasjon til smerte. Denne viser at ved stølhet så forsvinner smerten om man bedøver huden. Så selv om smerten oppleves som at den sitter i hele muskelen, så er det nervene helt ytterst i huden som faktisk responderer i smerteopplevelsen.

http://www.ncbi.nlm.nih.gov/pubmed/23562300

In DOMS state, there was no resting pain, but vibration reproducibly evoked pain (allodynia). The blockade of cutaneous C fibers abolished this effect, whereas it persisted during blockade of myelinated fibers. In the clinical subject, without exposure to eccentric exercise, vibration (and brushing) produced a cognate expression of CT-mediated allodynia. These observations attest to a broader role of CTs in pain processing.

This is the first study to demonstrate the contribution of CT fibers to mechanical allodynia in exercise-induced as well as pathological pain states. These findings are of clinical significance, given the crippling effect of sensory impairments on the performance of competing athletes and patients with chronic pain and neurological disorders.

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An investigation into the peripheral substrates involved in the tactile modulation of cutaneous pain with emphasis on the C-tactile fibres.

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Om hvordan hudens c-fibre spiller inn i smerte.

http://www.ncbi.nlm.nih.gov/pubmed/23604625 (kun abstract)

During cutaneous pain, vibration evoked a significant and reproducible increase in the overall pain intensity (allodynia). The blockade of myelinated fibres abolished the vibration sense, but the vibration-evoked allodynia persisted. Conversely, the blockade of unmyelinated cutaneous fibres abolished the allodynia (while the myelinated fibres were conducting or not). On the basis of these findings, in addition to our earlier work, we conclude that the allodynic effect of CT-fibre activation is not limited to nociceptive input arising from the muscle, but can be equally realized when pain originates in the skin. These results denote a broader role of CTs in pain modulation.

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Prevalence of Severe Hypovitaminosis D in Patients With Persistent, Nonspecific Musculoskeletal Pain

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Svært viktig studie som nevner hvordan d-vitamin har direkte sammenheng med ikke-spesifikke muskelsmerter. 98% av alle som fikk behandling for muskelplager hadde d-vitamin mangler, i gjennomsnitt 12 ng/ml (30nmol/L).

http://www.direct-ms.org/pdf/VitDNonAuto/VitaminDDeficiencyPain.pdf

All patients with persistent, nonspecific musculoskeletal pain are at high risk for the consequences of unrecognized and untreated severe hypovitaminosis D.

Because osteomalacia is a known cause of persistent, nonspecific musculoskeletal pain, screening all outpatients with such pain for hypovitaminosis D should be standard practice in clinical care.

Of the many types of chronic pain, nonspecific or idio- pathic musculoskeletal pain, such as noninflammatory arthritis, nonarticular rheumatism, and nonradicular low back pain, is seen frequently in medical and chiropractic clinics. Despite the prevalence, severity, and burdens of such pain, precise diagnosis and effective treatment are often elusive.

The prevalence of hypovitaminosis D was unexpectedly high in this population of nonelderly, nonhousebound, pri- mary care outpatients with persistent, nonspecific muscu- loskeletal pain refractory to standard pharmaceutical agents. Of all patients, 93% (140/150) had deficient levels of vitamin D (mean, 12.08 ng/mL; 95% confidence interval [CI], 11.18-12.99 ng/mL).

Unexpectedly, 100% of Af- rican American (n=22), 100% of American Indian (n=10), and 83% (29/35) of white patients with persistent pain also had hypovitaminosis D (mean, 11.7 ng/mL; 95% CI, 10.17- 13.27 ng/mL).

More than 90% of the patients in this study with persistent, nonspecific musculoskeletal pain were found to have deficient levels of 25-hydroxyvitamin D. Mean values were in the moderately severe to moderately deficient range. This was true regardless of immigrant status, sex, race, or season.

Even oral supplementation with vitamin D tablets may be inadequate at currently recommended doses.44-46 Up to 46% of persons found to be vitamin D–deficient have met the recommended daily intake.47-49 Also, oral supplements may not provide sufficient compensation for patients with existing hypovitaminosis D.50,51

These results support screening of all outpatients with persistent, nonspecific musculoskeletal pain for hypovitaminosis D. These patients are at high risk for the consequences of unrecognized and untreated hypovitaminosis D, and this risk extends to those now considered at low risk, including nonelderly, nonhousebound, or nonimmigrant persons of either sex

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Diaphragmatic Breathing Reduces Exercise-Induced Oxidative Stress

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Om hvordan diafragmisk pust (med magen) øker antioksidantbeskyttelsen og restitusjonen ved å senke kortison og øke melatonin. Gjort på et 24t sykkerlritt hvor de som gjorde 1t pusteing før de sovnet fikk raskere restitusjon. Nevner direkte sammenheng mellom kortisol og melatonin. Og påstår at pusten bør implementeres i ethvert treningsregime som restitusjon.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139518/

Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant

Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals.

Stress is defined as a physiological reaction to undesired emotional or physical situations. Initially, stress induces an acute response (fight or flight) that is mediated by catecholamines. When stress becomes chronic and lasts for a long time, the stressed organism reacts with physiological alterations to adapt to the unfavorable conditions. This ACTH-mediated reaction affects the immune and neuroendocrine systems, and it is responsible for several diseases [1]. Numerous data support the hypothesis that the pathophysiology of chronic stress can be due, at least partially, to an increase in oxidative stress [2–4], which may also contributes to heart disease [5,6], rheumatoid arthritis [7,8], hypertension [9,10], Alzheimer’s disease [11,12], Parkinson’s disease [13], atherosclerosis [14] and, finally, aging [15].

High levels of glucocorticoids are known to decrease blood reduced glutathione (GSH) and erythrocyte superoxide dismutase (SOD) activity in rats [20]. Other enzymes are also involved, and NADPH oxidase, xanthine oxidase and uncoupled endothelial nitric oxide synthase are important sources of reactive oxygen species (ROS) in glucocorticoid-induced oxidative stress (see [9] for a review on this argument).

Hormonal reactions to stressors, in particular plasma cortisol levels, are lower in people who meditate than in people who do not [31–36], suggesting that it is possible to modulate the neuroendocrine system through neurological pathways. Analysis of oxidative stress levels in people who meditate indicated that transcendental meditation, Zen meditation and Yoga correlate with lower oxidative stress levels [37–43].

Melatonin could also be involved in the reduction of oxidative stress because increased levels of this hormone have been reported after meditation [44–46]. This neurohormone is considered a strong antioxidant and is used as a treatment for aging. Melatonin in fact, increases several intracellular enzymatic antioxidant enzymes, such as SOD and glutathione peroxidase (GSH-Px) [47,48], and induces the activity of γ-glutamylcysteine synthetase, thereby stimulating the production of the intracellular antioxidant GSH (49]. A number of studies have shown that melatonin is significantly better than the classic antioxidants in resisting free-radical-based molecular destruction. In these in vivostudies, melatonin was more effective than vitamin E, β-carotene [50–52] and vitamin C [53–55].

Although it has been established that a continuous and moderate physical activity reduces stress, intense and prolonged exercise is deleterious and needs a proper recovery procedure.

Plasma cortisol levels increase in response to intense and prolonged exercise [60,61]. Ponjee et al. [62] demonstrated that cortisol increased significantly in male athletes after they ran a marathon. In another study, plasma ACTH and cortisol were found elevated in highly trained runners and in sedentary subjects after intense treadmill exercise [63].

Most, if not all, meditation procedures involve diaphragmatic breathing (DB), which is the act of breathing deeply into the lungs by flexing the diaphragm rather than the rib cage. DB is relaxing and therapeutic, reduces stress and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices.

Athletes were monitored during a training session for a 24-h long contest. This type of race lasts for 24h, generally starting at 10:00am and ending at 10:00am the following day. Bikers ride as many kilometers as possible on a specific circuit trail in the 24-h period. Athletes are allowed to stop, to sleep, to rest and to eat as much food as they want to eat.

Subjects of the studied group were previously trained to relax by performing DB and concentrating on their breath. These athletes spent 1h (6:30–7:30pm) relaxing performing DB in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. The only activity allowed was reading magazines. Lighting levels were monitored throughout the experiment and did not exceed 15 lux, a level well below that known to influence melatonin secretion [73,74].

As expected, the exercise induced a strong oxidative stress in athletes (Figure 1).

BAP (Biological Antioxidant Potential) levels were determined at different times, before and after exercise. Athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1h relaxing performing DB and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Since this test must be performed several hours after food ingestion, BAP levels were determined pre-exercise at 8:00am before breakfast, at 2:00am, and at 8:00am 24h post-exercise. Values shown are mean ± SD. *P < .05 DB versus control group. **P < .01 DB versus control group.

This study demonstrates that DB reduces the oxidative stress induced by exhaustive exercise. To our knowledge, this is the first study which explores the effect of DB on the stress caused by exhaustive physical activity.

The rationale is as follows (Figure 5)

  1. intense exercise increases cortisol production;
  2. a high plasmatic level of cortisol decreases body antioxidant defenses;
  3. a high plasmatic level of cortisol correlates with a high level of oxidative stress;
  4. DB reduces the production of cortisol;
  5. DB increases melatonin levels;
  6. melatonin is a strong antioxidant;
  7. DB increases the BAP and
  8. DB reduces oxidative stress.

If these results are confirmed in other intense physical activity programs, relaxation could be considered an effective practice to significantly contrast the free radical-mediated oxidative damage induced by intense exercise. Therefore, similar to the way that antioxidant supplementation has been integrated into athletic training programs, DB or other meditation techniques should be integrated into many sports as a method to improve performance and to accelerate recovery.

Hyperventilation, in fact, induces hyperoxia which is known to be related with oxidative stress [81,82]. The hyperventilation syndrome affects 15% of the population and occurs when breathing rates elevate to 21–23 bpm as a result of constricted non-DB. DB can treat hyperoxia and its consequences acting by two synergic ways: restoring the normal breath rhythm and reducing oxidative stress mainly through the increase in melatonin production which is known for its ability to reduce oxidative stress induced by exposure to hyperbaric hyperoxia [83].

Moreover, Orme-Johnson observed greatly reduced pathology levels in regular meditation practitioners [84,85]. A 5 years statistic of approximately 2000 regular participants demonstrated that Transcendental Meditation reduced benign and malignant tumors, heart disease, infectious diseases, mental disorders and diseases of the nervous system. Mourya et al. evidenced that slow-breathing exercises may influence autonomic functions reducing blood pressure in patients with essential hypertension [86]. Finally, there are also evidences that procedures which involve the control of the breathing can positively affect type 2 Diabetes [87], depression, pain [88], high glucose level and high cholesterol [89].

The role of melatonin must also be emphasized. Beyond its antioxidant properties, melatonin is involved in the regulation of the circadian sleep-wake rhythm and in the modulation of hormones and the immune system. Due to its wide medical implications, the increase in melatonin levels induced by DB suggests that this breath procedure deserves to be included in public health improvement programs.

DB increased the levels of melatonin in athletes, and this correlates with lower oxidative stress (ROMs), with lower cortisol levels and with the higher antioxidant status (BAP) in these athletes.

Tooley et al. [46] speculated that meditation-reduced hepatic blood flow [91] could raise the plasma levels of melatonin. Alternatively, since meditation increases plasma levels of noradrenaline [92] and urine levels of the metabolite 5HIAA [93], a possible direct action on the pineal gland could be hypothesized, as melatonin is synthesized in the pineal by serotonin under a noradrenaline stimulus [94]. More likely, we suspect that the increase in melatonin levels determined in our experiment can be mainly attributed to the reduced cortisol levels. Actually, a relationship between cortisol and melatonin rhythms has been observed [95], indicating that melatonin onset typically occurs during low cortisol secretion.

Overall, these data demonstrate that relaxation induced by DB increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol, which is known to negatively affect antioxidant defenses, and the increase in melatonin, a strong antioxidant. The consequence is a lower level of oxidative stress, which suggests that an appropriate recovery could protect athletes from long-term adverse effects of free radicals.

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Respiratory weakness in patients with chronic neck pain.

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Studie som nevner at alle med kroniske nakkeplager også har svake pustemuskler, og at pusten kan bidra til å opprettholde smertene. Spesielt ved svak utpust (MEP – maximal expiratory pressure) er det sammenheng med nakkesmerter. Kunne trengt hele denne studien.

http://www.ncbi.nlm.nih.gov/pubmed/23199797

Neck muscle strength (r > 0.5), kinesiophobia (r < -0.3) and catastrophizing (r < -0.3) were significantly associated with maximal mouth pressures (P < 0.05), whereas MEP was additionally negatively correlated with neck pain and disability (r < -0.3, P < 0.05).

It can be concluded that patients with chronic neck pain present weakness of their respiratory muscles. This weakness seems to be a result of the impaired global and local muscle system of neck pain patients, and psychological states also appear to have an additional contribution. Clinicians are advised to consider the respiratory system of patients with chronic neck pain during their usual assessment and appropriately address their treatment.

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Inflammation and the pathophysiology of work-related musculoskeletal disorders

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Viktig studie om betennelse og hvordan det påvirker muskler og annet vev i kroppen. Nevner gangen i prosessen: repetitiv muskelsammentrekning, økning i betennelsesfaktorer for å reprere, manglende restitusjon, økning i fibrøst vev (arrvev), kompresjon på nerver, myalgi, økt temperament, osv. Nevner også hvordan betennelser påvirker psyken; depresjon, nedsatt seksuallyst, tilbaketrekning, smerter, m.m. IL-6 gir utmattelse.

Den beskriver hvordan cytokiner sprøytet inn i mus gir «sickness behaviour» og hyperalgesi (økt smertesensitivitet). Studien her forholder seg mest til betennelser som følge av repetitive bevegelser, men dette utsagnet vil også tilsi at kosthold som øker pro-inflammatoriske cytokiner kan bidra til hyperalgesi.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1552097/

Results from several clinical and experimental studies indicate that tissue microtraumas occur as a consequence of performing repetitive and/or forceful tasks, and that this mechanical tissue injury leads to local and perhaps even systemic inflammation, followed by fibrotic and structural tissue changes.

We also propose a conceptual framework suggesting the potential roles that inflammation may play in these disorders, and how inflammation may contribute to pain, motor dysfunction, and to puzzling psychological symptoms that are often characteristic of patients with work-related MSDs.

Several recent clinical and experimental studies have been published indicating that inflammation plays a role in the development of tissue pathologies associated with these chronic disorders.

The US Department of Labor defines work-related MSDs as injuries or disorders of the muscles, nerves, tendons, joints, cartilage, and spinal discs associated with exposure to risk factors in the workplace. MSDs include sprains, strains, tears, back pain, soreness, pain, carpal tunnel syndrome, musculoskeletal system, or connective tissue diseases and disorders, when the event or exposure leading to the injury or illness is bodily reaction/bending, climbing, crawling, reaching, twisting; overexertion; or repetition (Bureau of Labor Statistics, 2005). Several risk factors are associated with the development or exacerbation of MSDs in the workplace, including physical, biomechanical, individual predisposition, and psychosocial conditions.

Psychosocial risk factors in the workplace also contribute to MSDs. These factors are associated with levels of workplace stress, such as job content and demands, job control, and social support (National Research Council, 2001). Non-workplace factors may also contribute to the development and exacerbation of MSDs, such as similar physical or high stress levels in the home. Certain past or present medical conditions also represent comorbid risk factors for MSDs (National Research Council, 2001).

Examples include past traumatic injury to the affected body part, systemic diseases that affect the musculoskeletal system, and diseases/disorders of the circulatory system. Women appear more susceptible than men to the development of MSDs, although this is highly industry-dependent. Advanced age or obesity may increase the impact of other risk factors on the severity of MSDs (National Research Council, 2001).

Musculotendinous injuries resulting from performing repetitive and/or forceful tasks are due to repeated overstretch, compression, friction, ischemia, and overexertion. We hypothesize that these injuries lead initially to an inflammatory response (Fig. 1). While the ultimate outcome of inflammation is to replace or repair injured tissues with healthy, regenerated tissue, Copstead and Banadki, 2000, when continued task performance is superimposed upon injured and inflamed tissue a vicious cycle of injury, chronic or systemic inflammation, fibrosis, and perhaps even tissue breakdown may occur. The end result is often pain and loss of motor function.


Schematic diagram showing three primary pathways hypothesized to lead to work-related musculoskeletal disorders caused by repetitive and/or forceful hand-intensive tasks: CNS reorganization (reviewed in Barr et al., 2004), tissue injury, or tissue reorganization.

Hirata et al. (2005) divided patients into symptom duration groups (<3, 4-7, 8-12, and >12 months).

  • Edematous changes were found in these tissues in patients of ❤ month duration.
  • Prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) were increased in patients of 4-7 month symptom duration,
  • while fibrotic changes were present in patients of longer symptom duration (>7 months).

PGE2 is a factor believed to cause vasodilation, edema, and enhancement of cytokines that induce synoviocyte proliferation, while VEGF is associated with endothelial and vascular smooth muscle cell proliferation during chronic inflammation. In Hirata’s study, both molecules peak in the intermediate phase (4-7 months) of CTS-induced tendosynovial changes and appear to contribute to tissue remodeling. Hirata postulates that since PGE2 is thought to regulate the production of several molecules, that it may regulate VEGF production in tenosynovium.

The increase in IL-6 is interesting. IL-6 has both inflammatory and anti-inflammatory properties, the latter primarily to suppress low-grade inflammation (Biffl et al., 1996). IL-6 is a tightly regulated cytokine normally not detectable in serum unless there is trauma, infection, or cellular stress, at which time IL-6 is an early cytokine responder. Pro-inflammatory effects of IL-6 include induction of cell growth and proliferation, and acute-phase responses, while its anti-inflammatory actions include inducing increases in serum IL-1 receptor antagonist and soluble TNF receptor (Biffl et al., 1996).

Trapezius muscle biopsies from male and female workers with either continuous or intermittent trapezius myalgia of at least 12 months duration show evidence of myopathic changes such as moth eaten and ragged, red type I muscle fibers, increased frequency of type II myofibers and atrophic myofibers consistent with muscle injury, and denervation/ischemic loss of muscle fibers, but no evidence of inflammation (Larsson et al., 2001). In contrast, Dennet and Fry (1988) examining the first dorsal interosseous muscle collected from 29 patients with painful chronic overuse syndrome found increased inflammatory cells as well as myopathic changes.

The first study, by Freeland et al. (2002) detected increased serum malondialdehyde, an indicator of cell stress, in patients with carpal tunnel syndrome, but no serum increases in PGE2, IL-1, or IL-6.

A recent study by Kuiper et al. (2005), examined serum for biomarkers of collagen synthesis and degradation (but not for biomarkers of injury or inflammation) in construction workers involved in heavy manual materials handling. Both collagen synthesis and degradation products were increased in workers involved in heavy manual tasks, although the overall ratio of synthesis to degradation products remained the same as in sedentary workers. Kuiper’s results suggest that tissues undergo adaptive growth responses that protect them from unresolved degradation.

In the third study, elevated plasma fibrinogen were present in subjects with low job control, linking perceived job stress with a biomarker of chronic inflammation (Clays et al., 2005).

a recently submitted study from our lab found increased pro-inflammatory cytokines in serum of patients with moderate and severe work-related MSD.

Archambault et al. (1997) observed hypercellularity, inflammatory cells, increased inflammatory cytokines, and increased mRNA of matrix molecules in the tendon by 6-8 weeks. When the kicking protocol was prolonged to 11 weeks, the inflammatory responses were apparently resolved. Instead, matrix reorganization processes, such as increased mRNA for collagen type III and matrix metalloproteinases, were observed (Archambault et al., 2001). Thus, in the higher demand kicking task, inflammation and tissue pathology were simultaneously present, while in the lower demand kicking task, inflammation preceeded matrix reorganization which may be a beneficial adaptive reorganization since no necrosis was observed.

In a series of studies, they report evidence of inflammation and angiogenesis (hypercellularity; increased COX-2 and VEGF mRNA) after 4 weeks of running at a rate of 17 m/min on a decline, 1 h/day for 5 days/week. These changes persisted through 16 weeks. They also found tendon thickening and reduced biomechanical tissue tolerance, changes that increased with continued exposure. Thus, repetitive tendon overuse is associated with inflammation. The tendon tissue is unable to launch a successful healing response due to continued use, and becomes fibrotic and structurally damaged.

These dose-dependent findings are similar to our recently submitted human study in which a systemic inflammatory mediator/marker response was greater in patients with moderate and severe MSD compared to mild.

In MSD, the primary causes of peripheral nerve trauma are over-stretch and compression of neuronal tissues during excursion (reviewed in Barr et al., 2004).

Animal models of chronic nerve constriction injury using ligatures show that chronic compression leads to an upregulation of intraneural inflammatory cytokines, fibrosis, Schwann cell death, axonal demyelination, and declines in electrophysiological function.
In our rat model, we found decreased nerve conduction velocity (NCV) in the median nerve at the wrist. By week 10 in HRLF rats, there was a small (9%) but significant decrease in NCV (Clark et al., 2003), demonstrating that nerve injury accumulates with continued task performance and leads to a clinically relevant loss of nerve function.

The association of motor behavioral changes with tissue changes in both our and Messner’s studies indicates that functional declines accompany tissue injury, inflammation and fibrosis/degeneration.

The psychoneuroimmunological effects of pro-inflammatory cytokines, specifically IL-1β, TNF-α, and IL-6, have been extensively studied in humans and in animal models over the past decade for their contribution to a constellation of physiological and behavioral responses known collectively as the “sickness behaviors”. This response includes fever, weakness, listlessness, hyperalgesia, allodynia, decreased social interaction and exploration, somnolence, decreased sexual activity, and decreased food and water intake (amply reviewed by Capuron and Dantzer, 2003; Wieseler-Frank et al., 2005). Sickness behaviors can be induced by administration of exogenous cytokines to animals, whether the cytokines were injected peripherally or centrally. One mechanism of action, the immune-to-brain communication through activation of brain and spinal cord glial cells was reviewed by Wieseler-Frank et al. (2005). Activation of CNS glia and subsequent production of inflammatory cytokines can lead to hyperalgesia.

Cohen et al. (1997) have also speculated that the elevation of serum IL-6 produces fatigue, which then may be responsible for decreases in an individual’s ability to perform functionally. The possibility for patients with chronic inflammatory conditions to succumb to the depressive effects of local and systemic pro-inflammatory cytokines has implications in the management of overuse MSDs.

Symptoms of depression, anxiety, heightened job stress, more anger with their employer, higher pain ratings, greater reactivity to pain, enhanced feelings of being overwhelmed by pain, and low confidence in problem solving abilities have been reported in numerous epidemiological and clinical studies of patients with MSDs (Clays et al., 2005; Gold et al., 2006; Shaw et al., 2002).

We hypothesize that performance of repetitive and/or forceful tasks may induce MSDs through three primary pathways: (1) CNS reorganization, (2) tissue injury, and (3) tissue reorganization.

The extent of these changes is dependent on task exposure (duration and level). A systemic response may be stimulated by cytokines released into the blood stream by injured tissues and immune cells. Circulating cytokines can stimulate global responses such as widespread increase in macrophages, local and distant tissue sensitization, and perhaps the induction of sickness behaviors, depression or anxiety, as may cytokine elevation in peripheral nerve tissues.

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Bench-to-bedside review: Carbon dioxide

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Om CO2 i helbredelse av vev. Viktig oversikt som nevner CO2 sin bane og effekt gjennom hele organismen – fra DNA til celle til vev til blod. Bekrefter ALT jeg har funnet om CO2 og pusteknikkene. Nevner også potensiell farer, som kun skjer ved akutt hypercapnia. Nevner også en meget spennende konsept om å buffre CO2 acidose med bikarbonat (Natron). I kliniske tilfeller på sykehus kan det ha negative effekter, men hos normale mennesker vil det virke som en effektiv buffer.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887152/

Hypercapnia may play a beneficial role in the pathogenesis of inflammation and tissue injury, but may hinder the host response to sepsis and reduce repair. In contrast, hypocapnia may be a pathogenic entity in the setting of critical illness.

For practical purposes, PaCO2 reflects the rate of CO2 elimination.

The commonest reason for hypercapnia in ventilated patients is a reduced tidal volume (VT); this situation is termed permissive hypercapnia.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887152/table/T1/?report=previmg

High VT causes, or potentiates, lung injury [4]. Smaller VT often leads to elevated PaCO2, termed permissive hypercapnia, and is associated with better survival [5,6]. These low-VT strategies are not confined to patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); they were first reported successful in severe asthma [7], and attest to the overall safety of hypercapnia. Indeed, hypercapnia in the presence of higher VT may independently improve survival [8].

Hypocapnia is common in several diseases (Table ​(Table1;1; for example, early asthma, high-altitude pulmonary edema, lung injury), is a common acid-base disturbance and a criterion for systemic inflammatory response syndrome [9], and is a prognostic marker of adverse outcome in diabetic ketoacidosis [10]. Hypocapnia – often prolonged – remains common in the management of adult [11] and pediatric [12] acute brain injury.

Table 1

Causes of hypocapnia

Hypoxemia Altitude, pulmonary disease
Pulmonary disorders Pneumonia, interstitial pneumonitis, fibrosis, edema, pulmonary emboli, vascular disease, bronchial asthma, pneumothorax
Cardiovascular system disorders Congestive heart failure, hypotension
Metabolic disorders Acidosis (diabetic, renal, lactic), hepatic failure
Central nervous system disorders Psychogenic/anxiety hyperventilation, central nervous system infection, central nervous system tumors
Drug induced Salicylates, methylxanthines, β-adrenergic agonists, progesterone
Miscellaneous Fever, sepsis, pain, pregnancy

CO2 is carried in the blood as HCO3-, in combination with hemoglobin and plasma proteins, and in solution. Inside the cell, CO2 interacts with H2O to produce carbonic acid (H2CO3), which is in equilibrium with H+ and HCO3-, a reaction catalyzed by carbonic anhydrase. CO2 transport into cells is complex, and passive diffusion, specific transporters and rhesus proteins may all be involved.

CO2 is sensed in central and peripheral neurons. Changes in CO2 and H+ are sensed in chemosensitive neurons in the carotid body and in the hindbrain [13,14]. Whether CO2 or the pH are preferentially sensed is unclear, but the ventilatory response to hypercapnic acidosis (HCA) exceeds that of an equivalent degree of metabolic acidosis [15], suggesting specific CO2 sensing.

An in vitro study has demonstrated that elevated CO2 levels suppress expression of TNF and other cytokines by pulmonary artery endothelial cells via suppression of NF-κB activation [18].

Furthermore, hypercapnia inhibits pulmonary epithelial wound repair also via an NF-κB mechanism [19].

The physiologic effects of CO2 are diverse and incompletely understood, with direct effects often counterbalanced by indirect effects.

Hypocapnia can worsen ventilation-perfusion matching and gas exchange in the lung via a number of mechanisms, including bronchoconstriction [21], reduction in collateral ventilation [22], reduction in parenchymal compliance [23], and attenuation of hypoxic pulmonary vasoconstriction and increased intrapulmonary shunting [24].

CO2 stimulates ventilation (see above). Peripheral chemoreceptors respond more rapidly than the central neurons, but central chemosensors make a larger contribution to stimulating ventilation. CO2increases cerebral blood flow (CBF) by 1 to 2 ml/100 g/minute per 1 mmHg in PaCO2[25], an effect mediated by pH rather than by the partial pressure of CO2.

Hypercapnia elevates both the partial pressure of O2 in the blood and CBF, and reducing PaCO2 to 20 to 25 mmHg decreases CBF by 40 to 50% [26]. The effect of CO2 on CBF is far larger than its effect on the cerebral blood volume. During sustained hypocapnia, CBF recovers to within 10% baseline by 4 hours; and because lowered HCO3-returns the pH towards normal, abrupt normalization of CO2 results in (net) alkalemia and risks rebound hyperemia.

Hypocapnia increases both neuronal excitability and excitatory (glutamatergic) synaptic transmission, and suppresses GABA-A-mediated inhibition, resulting in increased O2 consumption and uncoupling of metabolism to CBF [27].

Hypercapnia directly inhibits cardiac and vascular muscle contractility, effects that are counterbalanced by sympathoadrenal increases in heart rate and contractility, increasing the cardiac output overall [28].

Indeed, a large body of evidence now attests to the ability of hypercapnia to increase peripheral tissue oxygenation, independently of its effects on cardiac output [30,31].

The beneficial effects of HCA in such models are increasingly well understood, and include attenuation of lung neutrophil recruitment, pulmonary and systemic cytokine concentrations, cell apoptosis, and O2-derived and nitrogen-derived free radical injury.

Concern has been raised regarding the potential for the anti-inflammatory effects of HCA to impair the host response to infection. In early pulmonary infection, this potential impairment does not appear to occur, with HCA reducing the severity of acute-severe Escherichia coli pneumonia-induced ALI [41]. In the setting of more established E. coli pneumonia, HCA is also protective [42].

Hypocapnia increases microvascular permeability and impairs alveolar fluid reabsorption in the isolated rat lung, due to an associated decrease in Na/K-ATPase activity [47].

HCA protects the heart following ischemia-reperfusion injury.

Hypercapnia attenuates hypoxic-ischemic brain injury in the immature rat [52] and protects the porcine brain from reoxygenation injury by attenuation of free radical action. Hypercapnia increases the size of the region at risk of infarction in experimental acute focal ischemia; in hypoxic-ischemic injury in the immature rat brain, hypocapnia worsens the histologic magnitude of stroke [52] and is associated with a decrease in CBF to the hypoxia-injured brain as well as disturbance of glucose utilization and phosphate reserves.

Indeed, hypocapnia may be directly neurotoxic, through increased incorporation of choline into membrane phospholipids [56].

Rapid induction of hypercapnia in the critically ill patient may have adverse effects. Acute hypercapnia impairs myocardial function.

In patients managed with protective ventilation strategies, buffering of the acidosis induced by hypercapnia remains a common – albeit controversial – clinical practice.
While bicarbonate may correct the arterial pH, it may worsen an intracellular acidosis because the CO2 produced when bicarbonate reacts with metabolic acids diffuses readily across cell membranes, whereas bicarbonate cannot.

Hypocapnia is an underappreciated phenomenon in the critically ill patient, and is potentially deleterious, particularly when severe or prolonged. Hypocapnia should be avoided except in specific clinical situations; when induced, hypercapnic acidosis should be for specific indications while definitive measures are undertaken.

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Fibromyalgia is not all in your head, new research confirms

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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.»

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Pain

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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.

gatecontrolltheory

(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).

neuromatrixtheory

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.

bodyselfneuromatrix

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.