Neuroendocrinology and musculoskeletal dysfunction

- Fibromyalgia

Martin Krause

Fibromyalgia is a complex chronic pain condition. It is manifested by both peripheral and central changes in neuropeptide and immune markers. 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)

Tissue Acidosis

• 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)

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.

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.

more thyroid-superior cervical ganglion information regarding the relationship between the estrous cycle, the pituitary axis, pro-opiomelanocortin {being a compound for enkephalin, ACTH, & opioids}as well as the pineal gland 

PET imaging of hypothalamus and pain

Do high TSH values protect against chronic musculoskeletal complaints? The Nord-Troendelag Health Study (HUNT)

Knut Hagen ^a, ^b, , Trine Bjoro ^c, John-Anker Zwart ^a, ^b, ^d, Sven Svebak ^e, Gunnar Bovim ^a and Lars Jacob Stovner ^a, ^b

^aDepartment of Clinical Neuroscience, Section of Neurology, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway
^bNorwegian National Headache Centre, Trondheim, Norway
^cCentral Laboratory, The Norwegian Radium Hospital, and Hormone Laboratory, Aker University Hospital, Oslo, Norway
^dNational Centre for Spinal Disorders, St Olavs Hospital, Trondheim, Norway
^eDepartment of Public Health and General Practice, Faculty of medicine, Norwegian University of Science and Technology, Trondheim, Norway

Received 24 May 2004;  revised 20 November 2004;  accepted 2 December 2004.  AIB-400578.  Available online 2 February 2005.

Abstract

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.

Pain (2005), 113, 416-421

Predicting the failure of disc surgery by a hypofunctional HPA axis: evidence from a prospective study on patients undergoing disc surgery

Andrea Geiss ^a, , Nicolas Rohleder ^c, Clemens Kirschbaum ^c, Klaus Steinbach ^d, Heinz W. Bauer ^d and Fernand Anton ^a, <sup>b

a</sup> Department of Psychobiology, University of Trier, D-54286 Trier, Germany
^b Universite du Luxembourg, 162A, avenue de la Faiencerie, L-1511 Luxembourg
^c Biological Psychology, Technical University of Dresden, D-01062 Dresden, Germany
^d Klinik fuer Orthopaedie und Sportmedizin der Hochwald Kliniken, D-66709 Weiskirchen/Saarr, Germany

Received 24 May 2004;  revised 20 November 2004;  accepted 2 December 2004.  AIB-400578.  Available online 2 February 2005.

Abstract

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

Pain 114 (2005) 104-117

Physical and psychological factors predict outcome following whiplash injury

Michele Sterling ^a, , , Gwendolen Jull ^a, Bill Vicenzino ^a, Justin Kenardy ^b and Ross Darnell <sup>c

a</sup> The Whiplash Research Unit, Department of Physiotherapy, The University of Queensland, Brisbane, Qld 4072, Australia
^b Centre for National Research on Disability and Rehabilitation Medicine, School of Psychology, The University of Queensland, Brisbane, Qld 4072, Australia
^c School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, Qld 4072, Australia

Received 4 June 2004;  revised 23 November 2004;  accepted 7 December 2004.  AIB-400576.  Available online 21 January 2005.

Abstract

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 (<8 recovered, 10-28 mild pain and disability, >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.

Keywords: Whiplash injury; Physical and psychological factors; NDI scores; Prediction

Corresponding author. Tel.: +61 7 3365 4568; fax: +61 7 3365 2775.
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. 

see:

Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain

Peter J. Cabot , , ^a, ^b, ^d, Laurenda Carter ^a, ^b, Michael Sch?r ^a, ^b, ^c and Christoph Stein ^a, ^b, <sup>c

a</sup> Behavioral Pharmacology and Genetics Section, Intramural Research Program, NIDA/NIH, Baltimore, MD 21224, USA
^b Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD 21287-8711, USA
^c Klinik fuer Anaesthesiologie und Operative Intensivmedizin, Klinikum Benjamin Franklin, Freie Universitaet Berlin, Hindenburgdamm 30, D12200 Berlin, Germany
^d School of Pharmacy, The University of Queensland, St Lucia, Queensland, Australia 4072

Received 21 April 2000; revised 26 February 2001; accepted 29 March 2001 Available online 14 August 2001.

Abstract

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 - and -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.

Author Keywords: Opioid; Analgesia; Inflammation; Peripheral; Peptide; Lymphocyte

Corresponding author. Tel.: +61-7-3365-1376; fax: +61-7-3365-1688;

Pain (2001), 93, 207-212

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

Department of Psychology, University of Colorado at Boulder, Boulder, CO 80309, USA

Accepted 22 August 1995.  Available online 6 April 2000.

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 ^a, Elliot Sprecher ^b and David Yarnitsky ^a, ^b, ,

^a Technion Medical School, Rambam Medical Center, Haifa, Israel
^b Department of Neurology, Rambam Medical Center, Haifa 31096, Israel

Received 3 June 2004;  revised 14 October 2004;  accepted 15 November 2004.  AIB-400393.  Available online 25 December 2004.

Abstract

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

Pain (2005), 113, 354-359 

References

Apkarian et al (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain, 9, 463-484

Bush et al (2000) Cognitive and emotional influences in the anterior cingulate cortex. Trends Cogn Sci, 4, 215-222

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, 219-230.

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, 45-53

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, 311-327.

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, 229-239.

Sluka et al (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain, 129, 102-112.

Svensson et al (2003) Injection of NGF into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain, 104, 241-247.

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, 1240-1243.

Last update : 5 May 2009