Neuroendocrinology and Fibromyalgia
by Martin Krause
Fibromyalgia is a complex chronic pain condition. It is manifested by both peripheral and central changes in neuropeptide and immune markers. Experienced physiotherapy practitioners are realising the use of nutritional supplementation emphasises an holistic approach to the treatment of musculoskeletal injuries which results in quicker recovery, enhanced functioning as well the prevention of further injury.
Glucosamine (1200mg) and chondroitin sulphate (800mg) combine with methylsulfonylmethane (MSM) (800mg) are considered important in improving the production and/or size of hyaluronic acids as well as regulating the expression of matrix-degrading enzymes and their inhibitors. Furthermore, the concentration of sulphur in arthritic cartilage has been shown to drop to 1/3, thereby suggesting a role for MSM supplementation. High quality fish oils with an EPA and DHA concentrations of at least 1000mg is thought to have an inhibitory effect on arachidonic acid metabolism (Petra Hunt 2012, FX Medicine, 66, 10-11). Furthermore, fish oils anti-oxidating effect and it's balancing effect on hyperlipidemia suggests that it may have a role to play in tendon degeneration where immune-metabolic compromise has been found to be an important aspect of tendon degeneration and necrosis (see shoulder section elsewhere on this site). CoQ10 is also thought to help in the reduction of cholesterol and the enhancement of mitochondrial oxidative activity which, presumably, would also be good for tendons. Fish oils have also been associated with cognitive functioning, whose compromise can lead to irritability, depression and reduced immune function.
Compromised intestinal barrier function in people with food intolerances has been associated with inflammation at extraintestinal sites, including the joints. Evidence supports the relationship between the gastrointestinal microbiota, the mucosal and systemic immune responses and the development of arthritis. In fact glucosamine has been shown by A/Prof Luis Vitetta (Uni Qld) to have more favorable effects in patients with larger amounts of favorable enteric bacteria. Some new therapies include the use of pro-biotics in the treatment of joint disease.
Treatment of fibromyalgia has included the use of supplements such as Vitamin D, magnesium, malic acid and acetyl-L-Carnitine (Leng 2012, FX Medicine, 66, 16-17). To understand fibromyalgia we need to examine the mechanisms of pain.
Hyperexcitablity of the central nervous system due to activation of muscle nociceptors results in
- increased background neuronal activity
- increased responsiveness of the peripheral nerve
- appearance of new receptive fields (within minutes) in cortical areas
- spread of excitation to other spinal segments
Neurotransmitters and neuropeptides involved in myositis induced central sensitization include
- the activation of NMDA and NK-1 receptors which allows the expansion of the spinal target area (Hoheisel et al 1997)
- increased background activity in the dorsal horn due to the release of NO (nitrous oxide)
- Glutamate release magnesium which allows the influx of calcium. Na channels and AMPA/KA becomes active. NK1 cells are stimulated by substance P.
- Brain Derived Neurotrophic Factor (BDNF) activates TrkB receptors which stimulates PKA and PKC (protein kinase) release and phosphorylation (Mense & Hoheisel 2008)
Glial cells affect central sensitization through
- the release of pro-inflammatory cytokines, IL-1, TNF-alpha, BDNF - see Neuro-immuno-cognitive section of this website
Central sensitization induced by Nerve Growth Factor (NGF) which causes
- 'sterile inflammation' since it's release does not cause acute pain but does create long-lasting increase in subthreshold background activity leading to allodynia and hyperalgesia. This may be particularly important in repetitive occupations and in musicians. (Svensson et al 2003, Mense & Hoheisel 2008)
- NGF is likely to be involved with DOMS (Graven-Nielsen & Arendt-Nielsen 2008)
- low pH activates acid-sensing ion channels (ASICs). ASIC3 plays a key role in mechanical hyperalgesia induced my muscle insult. ASIC3 is found in DRG (dorsal root ganglion) innervating muscles (Sluka et al 2003). Application of pro-inflammatory cytokines (NGF, serotonin, IL-1beta, prostaglandin E2, bradykinin) to DRG cells mimics the increased ASIC3 mRNA seen after inflammation. Sluka et al (2007) concluded that activation of ASIC3 in the primary afferents innervating muscle is critical for the development of central sensitization after muscle insult and for consequent mechanical hyperalgesia.
Cytokines act on inflammation and repair through
- the balanced release between pro and anti-inflammatory cytokines
- soluble receptors (TNFsRII, IL-1RSII)
- decoy recpetors (IL-1RII) (Kopp & Alstergren 2008)
Sympathetic nervous system
- descending modulation
- genetic phenotypes predisposing to pain include a common single nucleotide polymorphism (SNP) in codon 158 of the COMT gene and has been associated with the perception of pain in humans (Zubieta et al 2003)
- inhibition of COMT (catechol-O-methyl transferase), a key enzyme which metabolizes catecholamines (adrenaline, noradrenaline) induces mechanical and thermal hyperalgesia and produces proinflammatory cytokines in rats. Blockade of Beta-adrenoreceptors diminishes clinical pain reported in a subpopulation with TMJD and FMS (Maixner 2008). This also reverse the suppression of the HPA axis (see below) by increasing the secretion of cortisol (Kizildere et al 2003)
- Muscle trauma from a bout of severe acute resistance training, in a group of well trained Finnish men and women, was shown to induce a neuroendocrine and immune systems response. Specifically, Leukocyte Beta-2-Adrenergic receptor expression was elevated on monocytes and granulocytes during the exercise, and elevated on lymphocytes during the recovery phase. These responses were thought to be under the control of adrenaline (epinephrine) and noradrenaline (norepinephrine) from peripheral sympathetic nerve terminals (Fragala et al 2011, Med Sc SP Ex, 43, 8, 1422-1432)
Serotonin, the 5HT1, 5HT2 and esp 5HT3 receptors may be involved in muscle pain and hyperalgesia (Ernberg 2008)
Pain - Motor interaction
- Lund et al (1993) suggested the pain-adaptation model to explain the interrelationship among activity in nociceptor afferents, a central pattern generator, motor function and co-ordination of muscles. This pain-adaptation model predicts increased muscle activity in the agonistic phases during muscle pain, thereby decreasing movement amplitude and velocity
Cerebral Processing of Muscle Pain
- prominent activation of the cerebellum and anterior cingulate cortex (ACC) and primary somatosensory cortes (S1) during muscle pain (Svensson et al 2008)
- increased 'interoception' via the right insular subserving the limbic sensory system (traditionally associated with emotion)
- the ACC has been associated with pain unpleasantness, with attention to pain, and with the motor component to the pain response (Apkarian et al 2005). The mid cingulate and more rostral perigenual activation is associated with the cognitive and affective divisions of the ACC resp (Bush et al 2000).
Conceptualised in Basel, Switzerland during 1991 (see references below)
Specifically, reduced response of the axis to stressors can result in alterations in hormonal responses during the luteal phase of the menstrual cycle.
People particular thought to be at risk are girls that have had amenorrhea, dysmenorrhea and/or late onset of menarchy.
Reduced Catecholamine Response to Exercise in Amenorrheic Athletes
SCHAAL, KARINE; VAN LOAN, MARTA D.; CASAZZA, GRETCHEN A.
Medicine & Science in Sports & Exercise. 43(1):34-43, January 2011.
Studies have found an array of endocrine disturbances related to energy deprivation in women with functional hypothalamic amenorrhea.
Purpose: We examined the catecholamine response to exercise in five eumenorrheic (EU) and five amenorrheic (AM) athletes, matched by age (mean ± SEM: EU = 29.8 ± 2.5 yr and AM = 31.0 ± 4.3 yr) and running volume (EU = 56.4 ± 8.1 km·wk-1 and AM = 61.5 ± 6.4 km·wk-1).
Methods: Subjects performed a maximal treadmill test followed by a 30-min recovery and then a submaximal running test, consisting of 4-min stages at 60%, 70%, and 80% and 15 min at 85% of peak oxygen consumption (V?O2peak). Blood was drawn after each stage to measure glucose, lactate, epinephrine, norepinephrine, and cortisol concentrations. HR, blood pressure, and rate of perceived exertion were also measured at each stage.
Results: There were no differences between groups in body composition or V?O2peak (EU = 57.3 ± 2.3 mL·kg-1·min-1 and AM = 54.1 ± 1.2 mL·kg-1·min-1). Resting HR and mean arterial pressure were significantly (P ? 0.05) lower in AM. Norepinephrine was lower in AM at 70%, 80%, 85%, and 100% of V?O2peak (EU = 7784.5 ± 582.9 pg·mL-1 and AM = 3626.1 ± 271.4 pg·mL-1 at V?O2peak). Epinephrine (EU = 1470.3 ± 275.1 pg·mL-1 and AM = 416.9 ± 67.5 pg·mL-1) and blood lactate (EU = 10.1 ± 1.2 mmol·L-1 and AM = 6.7 ± 0.9 mmol·L-1) were lower at V?O2peak in AM.
Conclusions: Our results demonstrate a reduced adrenergic response to intense exercise in AM athletes as indicated by reduced blood lactate and catecholamine concentrations. A suppressed catecholamine response could decrease performance by reducing the sympathetic drive essential for the cardiovascular and metabolic adjustments needed to maintain high intensities of exercise.
Additionally, people who have undergone cervical trauma to the peripheral cervical sympathetic ganglia may also be predisposed to FM, and Chronic Fatigue which could lead to stress fractures.
Finally, there appears to be a correlation between the function of the sympathetic nervous system and the thyroid gland. Hypo/hyperthyroidism may also predispose people to musculoskeletal dysfunction and injury.
Alteration of cortical excitability in patients with fibromyalgia
Alaa Mhalla, Daniel Ciampi de Andrade, Sophie Baudica, Serge Perrotacd, Didier Bouhassira
We assessed cortical excitability and intracortical modulation systematically, by transcranial magnetic stimulation (TMS) of the motor cortex, in patients with fibromyalgia. In total 46 female patients with fibromyalgia and 21 normal female subjects, matched for age, were included in this study. TMS was applied to the hand motor area of both hemispheres and motor evoked potentials (MEPs) were recorded for the first interosseous muscle of the contralateral hand. Single-pulse stimulation was used for measurements of the rest motor threshold (RMT) and suprathreshold MEP. Paired-pulse stimulation was used to assess short intracortical inhibition (SICI) and intracortical facilitation (ICF). Putative correlations were sought between changes in electrophysiological parameters and major clinical features of fibromyalgia, such as pain, fatigue, anxiety, depression and catastrophizing. The RMT on both sides was significantly increased in patients with fibromyalgia and suprathreshold MEP was significantly decreased bilaterally. However, these alterations, suggesting a global decrease in corticospinal excitability, were not correlated with clinical features. Patients with fibromyalgia also had lower ICF and SICI on both sides, than controls, these lower values being correlated with fatigue, catastrophizing and depression. These neurophysiological alterations were not linked to medication, as similar changes were observed in patients with or without psychotropic treatment. In conclusion, fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome. Our data add to the growing body of evidence for objective and quantifiable changes in brain function in fibromyalgia.
Do high TSH values protect against chronic musculoskeletal complaints? The Nord-Troendelag Health Study (HUNT)
Knut Hagen, Trine Bjoro, John-Anker Zwart, Sven Svebak, Gunnar Bovim and Lars Jacob Stovner
The aim of this large cross-sectional population-based study was to examine a possible positive or negative association between thyroid dysfunction and chronic musculoskeletal complaints (MSC). Between 1995 and 97, all 94,197 adults in Nord-Trondelag County in Norway were invited to participate in a health survey. A total of 64,787 (69%) responded to questions related to MSC, whereof thyroid-stimulating hormone (TSH) was measured in 34,960 individuals. These included a 5% random sample of women and men 20 - 40 years of age ( n =2165), nearly all women above 40 ( n =19,308), a random sample which included 50% of men older than 40 years ( n =9983), and 3504 (97%) with self-reported thyroid dysfunction. Among the 64,787 participants, 30,158 (47%) who reported MSC continuously for at least 3 months during the past year where defined as having chronic MSC. Associations between thyroid dysfunction and chronic MSC were assessed in multivariate analyses, estimating prevalence odds ratios (ORs) with 95% confidence intervals (CIs). High TSH values were associated with lower prevalence of chronic MSC at ten anatomical sites among women with no history of thyroid dysfunction. Among these, chronic MSC was less likely (OR=0.6, 95% CI 0.4?0.8) if TSH =10 mU/L than in women with normal TSH (0.2 - 4 mU/L). Chronic MSC was less likely among women with high TSH values. The mechanism is unclear and, theoretically, may reflect a fundamental gender-specific relationship between TSH and pain perception in the central nervous system.
Predicting the failure of disc surgery by a hypofunctional HPA axis: evidence from a prospective study on patients undergoing disc surgery
Andrea Geiss, Nicolas Rohleder, Clemens Kirschbaum, Klaus Steinbach, Heinz W. Bauer and Fernand Anton
Patients with postoperative ongoing sciatic pain have been shown to exhibit reduced cortisol levels along with enhanced IL-6 levels. The aim of the present study was to clarify the relationship between a reduced cortisol secretion and enhanced cytokine levels by performing a prospective study on patients with disc herniation. Twenty-two patients were examined before and after their disc surgery. Twelve healthy, pain-free subjects matched for age, education and gender constituted the control group. The preoperative examinations included the assessment of the diurnal pattern of cortisol secretion and the feedback sensitivity of the hypothalamus-pituitary-adrenal (HPA) axis. Patients' subjective stress levels also were assessed during the preoperative examination. The diurnal pattern of cortisol secretion was again assessed during the postoperative examination. Furthermore, blood samples were collected to measure catecholamine, adrenocorticotropic hormone (ACTH)- and interleukin-6 (IL-6) levels before and after measuring the pressure pain thresholds (PPTs). An assessment of the sensitivity of circulating monocytes to the immunosuppressive effects of glucocorticoids was further included in the postoperative examinations. Failed back syndrome (FBS) patients ( n =12) showed a reduced cortisol secretion in the morning hours and enhanced feedback sensitivity of the HPA axis. Furthermore, FBS patients displayed an increased in-vitro production of proinflammatory cytokines and a relative glucocorticoid resistance of pro-inflammatory cytokine producing monocytes as compared to non-FBS patients ( n =10) and controls. After PPT measurement FBS patients exhibited an increased norepinephrine but decreased epinephrine response, together with lower ACTH levels and a four times higher plasma IL-6 response. These findings suggest that chronically stressed patients are at a higher risk for a poor surgical outcome as their reduced cortisol secretion promotes the postoperative ongoing synthesis of proinflammatory cytokines.
Keywords: Sciatic pain; Hypothalamus-pituitary-adrenal axis; Localized glucocorticoid resistance; Proinflammatory cytokines; Chronic stress
Physical and psychological factors predict outcome following whiplash injury
Michele Sterling , Gwendolen Jull, Bill Vicenzino, Justin Kenardy and Ross Darnell
Predictors of outcome following whiplash injury are limited to socio-demographic and symptomatic factors, which are not readily amenable to secondary and tertiary intervention. This prospective study investigated the predictive capacity of early measures of physical and psychological impairment on pain and disability 6 months following whiplash injury. Motor function (ROM; kinaesthetic sense; activity of the superficial neck flexors (EMG) during cranio-cervical flexion), quantitative sensory testing (pressure, thermal pain thresholds, brachial plexus provocation test), sympathetic vasoconstrictor responses and psychological distress (GHQ-28, TSK, IES) were measured in 76 acute whiplash participants. The outcome measure was Neck Disability Index scores at 6 months. Stepwise regression analysis was used to predict the final NDI score. Logistic regression analyses predicted membership to one of the three groups based on final NDI scores (30 moderate/severe pain and disability). Higher initial NDI score (1.007-1.12), older age (1.03-1.23), cold hyperalgesia (1.05-1.58), and acute post-traumatic stress (1.03-1.2) predicted membership to the moderate/severe group. Additional variables associated with higher NDI scores at 6 months on stepwise regression analysis were: ROM loss and diminished sympathetic reactivity. Higher initial NDI score (1.03-1.28), greater psychological distress (GHQ-28) (1.04-1.28) and decreased ROM (1.03-1.25) predicted subjects with persistent milder symptoms from those who fully recovered. These results demonstrate that both physical and psychological factors play a role in recovery or non-recovery from whiplash injury. This may assist in the development of more relevant treatment methods for acute whiplash.
Pain Journal , 114, 141-148
The immune system affects the neuroendocrine system through substances called cytokines (cyto = cell, kine = movement). These cytokines include Interleukin-1, Interleukin-6, and Tumor Necrosis Factor alpha. The cytokines communicate messages between the brain and the body and are considered to be regulated by the sympathetic nervous system. An imbalance in the regulation of the immune system may activate and/or perpetuate inflammation. Conversely, chronic inflammation may activate the immune system and affect hormonal regulation of the neuroendocrine system. Muscles may represent a potent reservoir of proteins which can be used by the immune system for fighting infection and inflammation. Additionally, heat shock proteins represent an important aspect of inflammation and repair, as they represent the most primitive 'building blocks' for the restoration of the cytoskeleton as well as being involved with T-lymphocyte activity. REDOX , anti-oxidant behaviour also occurs as a result of muscular metabolic activity. The production of glutamine inside muscles aids in the liver and kidney's function as anti-oxidant organs. Finally, the sympathetic nervous system innervates the lymphatic glands and hence could play a role in the resolution of both inflammation and infection.
Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain
Peter J. Cabot, Laurenda Carte, Michael Schur and Christoph Stein
We have previously shown that -endorphin (END) is contained and released from memory-type T-cells within inflamed tissue and that it is capable to control pain (J Clin Invest 100(1) (1997) 142). Methionine-enkephalin (MET) and Dynorphin-A (DYN) are endogenous opioids with preference for -opioid receptors, respectively. Both MET and DYN are produced and contained within immune cells. The goal of this study was to determine the release characteristics of MET and DYN in a rat model of localized hindpaw inflammation and to examine the antinociceptive role of MET and DYN in a Freund's adjuvant induced model of inflammatory pain. We found that corticotropin-releasing factor (CRF) can stimulate the release of both MET and DYN from lymphocytes. This release is dose-dependent and reversible by the selective CRF antagonist -helical-CRF. Furthermore, CRF (1.5 ng) produces analgesia when injected into the inflamed paw, which is reversible by direct co-administration of antibodies to MET. Lymphocyte content of MET was 7.0 + 1.4 ng/million cells, whilst DYN content was ~30-fold lower. Both END and DYN, but not MET, were released by IL-1. Consistently, IL-1 produced peripheral analgesic effects which were not reversed by antibodies to MET. These results indicate that both MET and DYN play a role in peripheral analgesia but have different characteristics of release. These studies further support a role of the immune system in the control of inflammatory pain. This may be particularly important in patients suffering from compromised immune systems as with cancer and AIDS.
Interestingly, IL-1 has been linked with the vagal nerve as the messenger to tractus solitarus
Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states
Linda R. Watkins, Steven F. Maier and Lisa E. Goehler
Pain (1995), 63, 289-302
In concordance with the above hypothesis it has recently been demonstrated that vagal afferents exert an inhibitory effect on somatic pain.
Vagal stomach afferents inhibit somatic pain perception
Oshra Sedan, Elliot Sprecher and David Yarnitsky
Vagal stimulation inhibits systemic pain perception in animals, probably via the nucleus tractus solitarius and its connections with descending nuclei in the brainstem which inhibit pain. Pain-inhibiting effects of such stimulation in humans, obtained from epileptic patients treated by vagal stimulation, are controversial. The aim of our study was to evaluate whether vagal stomach afferent activation inhibits pain perception in healthy humans. Pain thresholds, magnitude of tonic heat pain at 46C stimulation, pain temporal summation and laser pain evoked potentials were measured at the hand before and immediately after rapid drinking of 1500 ml water in 31 volunteers. We found an increase in heat pain threshold from 43.3 + 2.6 to 44.7 + 2.2C, P <0.0001, a decrease of peak pain magnitude to tonic heat from 56.3 + 26.2 to 43.7 + 25.8 (on 0-100 VAS), P <0.0001, a lowering of area under the curve during tonic noxious heat stimulus from 1962 + 984 to 1411 + 934, P <0.001. Additionally, we observed a decrease in the peak to peak evoked potential amplitude from 19.2 µV + 1.2 to 15.6 µV + 1.2 ( P =0.005) together with a decrease in the estimation of mean laser induced pain from 52.28 + 18.00 to 48.14 + 20.18 ( P =0.025). Mechanical pain thresholds and temporal summation did not change significantly. We conclude that vagal stomach afferents exert an inhibitory effect on somatic pain perception in humans.
Keywords: Vagus; Pain; Parasympathetic
Apkarian et al (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain, 9, 463 to 484
Bush et al (2000) Cognitive and emotional influences in the anterior cingulate cortex. Trends Cogn Sci, 4, 215 to 222
Ernberg (2008) Serotonergic receptor involvement in muscle pain and hyperalgesia. In Fundamentals of Musculoskeletal Pain, ch10, IASP Press, Seattle
Graven-Nielsen & Arendt-Nielsen (2008) Human models and clinical manifestations of musculoskeletal pain and pain-motor interactions. In Fundamentals of Musculoskeletal Pain, ch11, IASP Press, Seattle
Hoheisel et al (1997) Myositis-induced functional reorganisation of the rat dorsal horn: affects of spinal superperfusion of antagonists to neurokinin and glutamate receptors. Pain, 1997, 69, 219 to 230.
Kizildere et al (2003) During a Corticotropin-releasing hormone test in healthy subjects, administration of a beta-adrenergic antagonist induced secretion of cortisol and dehydroepiandrosterone sulfate and inhibited secretion of ACTH, Eur J Endocrinology, 148, 45 to 53
Kopp & Alstergren (2008) Peripheral aspects of cytokines in musculoskeletal pain. In Fundamentals of Musculoskeletal Pain, ch9, IASP Press, Seattle
Lund et al (1993) The relationship between pain and muscle activity in fibromyalgia and similar conditions. In Vaeroy & Merskey. Progress in fibromyalgia and myofascial pain. Amsterdam, Elsevier, 311 to 327.
Maixner (2008) Biopsychological and genetic risk factors for TMJ disorders and related conditions. In Fundamentals of Musculoskeletal Pain, ch17, IASP Press, Seattle
Mense & Hoheisel (2008) Mechanisms of cnetral nerous hyperexcitability due to activation of muscle nociceptors. In Fundamentals of Musculoskeletal Pain, ch5, IASP Press, Seattle
Sluka et al (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain, 106, 229 to 239.
Sluka et al (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain, 129, 102 to 112.
Svensson et al (2003) Injection of NGF into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain, 104, 241 to 247.
Svensson & Abrahamsen (2008) Central representation of muscle pain and hyperalgesia. In Fundamentals of Musculoskeletal Pain, ch12, IASP Press, Seattle
Zubieta et al (2003) COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 299, 1240 to 1243.
Last update : 19 July 2012