CNS Spectr. 2008;13:3(suppl 5):12-17

Funding for this activity has been provided by educational grants from Eli Lilly and Company and Pfizer Inc.

Faculty Affiliations and Disclosures

Dr. Staud is professor of medicine in the Division of Rheumatology and Clinical Immunology, McKnight Brain Institute, at the University of Florida in Gainesville. Dr. Spaeth is medical director of the Center for Clinical Rheumatology Research in Graefelfing/Munich, Germany.

Disclosures: Dr. Staud is a consultant to Eli Lilly, Jazz, and Pfizer; is on the speaker’s bureau of Merck; and is supported by National Institutes of Health grants NS-38767 and AR053541. Dr. Spaeth is a consultant to Allergan, Eli Lilly, Jazz, and Pierre Fabre Medicament; and is on the speaker’s bureaus of Eli Lilly and Pierre Fabre Medicament.

Submitted for publication: January 2, 2008; Accepted for publication: February 18, 2008.

Please direct all correspondence to: Roland Staud, MD, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0221; Tel: 352-273-5346; Fax: 352-392-8483; E-mail: staudr@ufl.edu.

Abstract 

Fibromyalgia pain is frequent in the general population, but its pathogenesis is only partially understood. Patients with fibromyalgia lack consistent tissue abnormalities but display features of hyperalgesia (increased sensitivity to painful stimuli) and allodynia (lowered pain threshold). Many recent fibromyalgia studies have demonstrated central nervous system (CNS) pain processing abnormalities, including abnormal temporal summation of pain. In the CNS, persistent nociceptive input from peripheral tissues can lead to neuroplastic changes resulting in central sensitization and pain. This mechanism appears to represent a hallmark of fibromyalgia and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established, only minimal peripheral input is required for the maintenance of the chronic pain state. Additional factors, including pain-related negative affect and poor sleep have been shown to significantly contribute to clinical fibromyalgia pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of fibromyalgia and other chronic pain syndromes.

Introduction

Fibromyalgia patients consistently complain of pain in the musculature but do not show evidence of consistent tissue abnormalities. Many recent studies have demonstrated that fibromyalgia pain is related to sensitization of central nervous system (CNS) pain pathways. The pathogenesis of fibromyalgia is unknown, although abnormal concentration of CNS neuropeptides, biogenic amines, and alterations of the hypothalamic-pituitary-adrenal (HPA) axis have been described.^1-4 There is a large body of evidence supporting a generalized lowering of pressure pain thresholds in fibromyalgia patients.^5-9 Importantly, the mechanical pain hypersensitivity (allodynia) of fibromyalgia patients is not limited to tender points but appears to be widespread.⁹ In addition, almost all studies of fibromyalgia patients have shown abnormalities of pain sensitivity while using different methods of sensory testing. Emotions, sociocultural influences, beliefs, and biases strongly influence pain.

In general, abnormalities of pain processing appear to play an important role in fibromyalgia pain, particularly those related to deep tissue impulse input, central sensitization, and negative affect. Particularly, alterations of central pain processing, including increased temporal summation of pain (or windup) and central sensitization appear to be relevant to clinical fibromyalgia pain.

Pathogenesis of Fibromyalgia Pain

Fibromyalgia is a pain amplification syndrome of patients who are highly sensitive to painful and non-painful stimuli, including touch, heat, cold, chemicals, light, sound, and smell. The cause for the heightened sensitivity of fibromyalgia patients is unknown. Most fibromyalgia patients show blunting of the HPA responses to stressors^10,11 as well as increased levels of substance P (SP),^1,12 excitatory amino acids,¹³ and neurotrophins¹⁴ in the cerebrospinal fluid (CSF).

Substance P and Serotonin

SP is an 11-amino-acid neuropeptide which acts as a neuromodulator via the neurokinin-1 (NK1) receptor. Several studies have reported increased SP concentrations in the CSF of fibromyalgia patients.^1,3,15,16 SP sensitizes dorsal horn neurons to the effects of other neuromodulators and CSF SP levels of fibromyalgia patients seem to correlate with pain severity over time.¹⁷ Elevations of SP in the CSF, however, are not specific to fibromyalgia. Other chronic pain syndromes, such as lower-back pain and painful neuropathy, often present with high CSF levels of SP.^18-20 High CSF concentrations of SP, however, represent the most prominent neurochemical abnormality found in fibromyalgia patients. Significant negative correlations also exist between levels of SP and serotonin (5-HT), its precursor tryptophan (TRP), and its primary metabolite 5-HIAA, in the serum of patients with fibromyalgia.²¹ High serum concentrations of 5-HIAA and  TRP show a significant relation with low pain scores. In contrast, low levels of 5-HIAA and high concentrations of SP are both positively correlated with severe sleep disturbances.²²

Nerve Growth Factor and Other Neurotransmitters

Nerve growth factor (NGF), which stimulates the production of SP in small afferent unmyelinated neurons, was found to be elevated in the CSF of patients with primary fibromyalgia, but not in fibromyalgia patients with associated painful inflammatory conditions (secondary fibromyalgia).²³ This finding suggests that subgroups of fibromyalgia patients utilize different pain mechanisms. Although elevated CSF SP may represent a common link between primary and secondary fibromyalgia, both groups seem to utilize different pathways that result in increased SP levels. In primary fibromyalgia NGF produced by central interneurons seems to increase SP. In secondary fibromyalgia the inflammation characteristic for the underlying rheumatic or infectious conditions appears to be responsible for the elevated CSF SP. For these reasons, NGF could be critical for the initiation and/or perpetuation of painful symptoms of primary but not secondary fibromyalgia.²³ Furthermore, central sensitization is associated with the release of excitatory amino acids such as glutamate (GLU), which interacts both with its receptor and with neuropeptides such as SP and NGF.

Hypothalamic Pituitary Adrenal Axis Abnormalities in Fibromyalgia

 The HPA axis is part of an adaptive system that responds to stressors such as pain and trauma as well as physiologic stressors. Note that corticotrophin-releasing hormone (CRH) is the key regulator of the HPA axis. Detailed functional studies of the HPA axis provided mixed results in fibromyalgia.^10,24-26 Though clearly dysfunctional, the abnormal HPA axis responses of fibromyalgia patients have been explained with either increased²⁶ or decreased CRH neuronal activity.^27,28 Elevated levels of CRH have been detected in the CSF of fibromyalgia patients.²⁹ It is known that CRH neurons in the hypothalamus receive synaptic input from 5-HT neurons projecting from the midbrain raphe nuclei. In vitro 5-HT can stimulate the release of CRH from isolated rat hypothalamus³⁰ through receptor subtypes that can modulate adrenocorticotropic hormone and cortisol production.³¹ Although the mechanisms of the HPA axis abnormalities in fibromyalgia are not completely understood, increasing evidence supports the crucial role of 5-HT for its function.

Role of Afferent Input in Fibromyalgia Pain

Although most previous fibromyalgia studies did not show consistent peripheral tissue abnormalities³² more recent evidence points to possibly relevant alterations in skin and muscles.^33-38 These peripheral changes may contribute to increased tonic nociceptive input into the spinal cord that results in augmented pain processing and central sensitization. In addition, there is compelling evidence for the contribution of peripheral pain to overall clinical pain in fibromyalgia.³⁹ Importantly, nociceptive activity in peripheral tissues of fibromyalgia patients does not need to be extensive, because central sensitization requires little sustained input for the maintenance of the sensitized state and chronic pain.³⁹

Despite increasing evidence emphasizing the role of sensory abnormalities for chronic widespread pain in fibromyalgia, the contribution of psychological factors to fibromyalgia pain must also be recognized. Self-reported depression at baseline was associated with a more than six-fold increased likelihood of reporting fibromyalgia symptoms at follow-up and was found to be the strongest independent predictor.⁴⁰ In addition, psychosocial factors including high levels of distress, fatigue, and frequent healthcare-seeking behavior are strong predictors for chronic widespread pain and fibromyalgia.⁴¹

In this context, several studies have reported fibromyalgia to be comorbid with major depressive disorder (MDD).^42,43 A recent large family study of fibromyalgia patients showed that fibromyalgia and MDD shared familial risk factors,⁴⁴ emphasizing the strong relationship between negative affect and fibromyalgia pain.

Peripheral and Central Sensitization

Although heightened pain sensitivity is a hallmark of fibromyalgia, little is known about the genetic and other factors that contribute to this abnormality. Particularly, tissue sensitization after injury has long been recognized as providing an important contribution to pain. This form of sensitization is related to heightened sensitivity of primary nociceptive afferents (peripheral sensitization), whereas central sensitization requires functional changes in the CNS (neuroplasticity). Central sensitization can manifest itself in several ways, including increased excitability of spinal cord neurons, enlargement of their receptive fields, reduction in pain threshold, and/or recruitment of novel afferent inputs. Behaviorally, centrally sensitized patients like fibromyalgia sufferers report abnormal or heightened pain sensitivity to innocuous or painful stimuli with spreading of hypersensitivity to uninjured sites and the generation of pain by low threshold mechanoreceptors that are normally silent in pain processing. Thus, tissue injury may not only result in afferent nociceptive input but also expansion of dorsal horn receptive fields and central sensitization.

Central sensitization, which can occur as an immediate or delayed phenomenon,⁴⁵ is associated with increased sensitivity of wide dynamic range and nociception-specific neurons of the spinal cord. Whereas delayed central sensitization mostly depends on transcriptional and translational neuronal changes during afferent barrage, immediate central sensitization relies on dorsal horn receptor mechanisms, including the N-methyl-D-aspartate (NMDA) and NK1 receptors.⁴⁶ Functional magnetic resonance imaging (fMRI) studies of pain-related brain activity has been used to show increased central pain sensitivity. Several fMRI studies demonstrated mechanical hyperalgesia (tested by computerized, standardized pressure application) in fibromyalgia patients as compared with controls.⁴⁷

Pain Amplification

Peripheral nociceptors can become increasingly sensitive after tissue trauma and/or after upregulation of nociceptor expression in peripheral nerve endings. Subsequent activation of these receptors will result in increased neuronal firing and pain. Although only supported by indirect evidence at this time, peripheral pain mechanisms seem to play an important role in fibromyalgia pain.³⁹ Impulses from peripheral nociceptors are transmitted to the central nervous system by myelinated Aδ (first pain) and unmyelinated C-fibers (second pain). Aδ-mediated pain signals are rapidly conducted to the central nervous system (~10 meters/second), whereas C-fiber impulses travel relatively slowly (~1.6 meter/second). When the distance of C-fiber transmission is sufficiently long (like the length of an extremity) this delay of C-fiber, compared to Ab fiber, impulses can be easily detected by study subjects. An important test of central pain amplification that takes advantage of this phenomenon is temporal summation of second pain or windup (WU).⁴⁸ This technique reveals sensitivity to input from unmyelinated (C) afferents and the status of the NMDA receptor system.⁴⁹ Both are implicated in a variety of chronic pain conditions. Thermal, mechanical, or electrical WU stimuli can be applied to the skin or musculature of patients and commercial neurosensory stimulators are readily available for WU testing.

Windup is Abnormal in Fibromyalgia

Recent investigations in fibromyalgia patients have focused on WU and central sensitization because this chronic pain syndrome is associated with extensive secondary hyperalgesia and allodynia.⁵⁰ Several studies provided psychophysical evidence that input to central nociceptive pathways is abnormal in fibromyalgia patients.^48,51-55 When WU pain is evoked both in fibromyalgia patients and in normal controls, the perceived pain increase by experimental stimuli (mechanical, heat, cold, or electricity) is greater for fibromyalgia patients compared with control subjects, as is the magnitude of temporal summation or WU within a series of stimuli (Figure). Following a series of stimuli, WU aftersensations are also increased, last longer, and are more frequently painful in fibromyalgia subjects. These results indicate both augmentation and prolonged decay of nociceptive input in fibromyalgia patients and provide convincing evidence for a role for central sensitization in the pathogenesis of this syndrome. There are several important points that appear relevant for clinical practice. As previously mentioned, when central sensitization has occurred in chronic pain patients, little additional nociceptive input is required to maintain the sensitized state. Thus, seemingly innocuous daily activities may contribute to the maintenance of chronic pain. In addition, the decay of painful sensations is prolonged in fibromyalgia resulting in slow reductions of their pain levels during rest as well as brief therapeutic interventions. Many frequently used analgesic medications do not improve central sensitization, and some medications, including opioids, have been shown to maintain or even worsen this CNS phenomenon.

Windup Measures Can Predict Fibromyalgia Pain Intensity

The important role of central pain mechanisms for clinical pain is also supported by their usefulness as predictors of clinical pain intensity of fibromyalgia patients. Thermal WU ratings correlate well with clinical pain intensity (Pearson’s r=.53), thus emphasizing the important role of this pain mechanism for fibromyalgia. In addition, hierarchical regression models that include tender point count, pain-related negative affect, and WU ratings have been shown to account for 50% of the variance in fibromyalgia clinical pain intensity.⁵⁶

Mechanisms of Abnormal Pain Sensitivity in Fibromyalgia

The mechanisms underlying the central sensitization that occurs in patients with fibromyalgia relies on hyperexcitability of spinal dorsal horn neurons that transmit nociceptive input to the brain. As a consequence, low intensity stimuli delivered to the skin or deep muscle tissue generate high levels of nociceptive input to the brain as well as the perception of pain. Specifically, intense or prolonged impulse input from Aβ and C afferents sufficiently depolarizes the dorsal horn neurons and results in the removal of the Mg²⁺ block of NMDA-gated ion channels. This is followed by the influx of extracellular Ca²⁺ and production of nitric oxide, which diffuses out of the dorsal horn neurons. Nitric oxide, in turn, promotes the exaggerated release of excitatory amino acids and SP from presynaptic afferent terminals and causes the dorsal horn neurons to become hyperexcitable. Subsequently, low intensity stimuli evoked by minor physical activity may be amplified in the spinal cord resulting in painful sensations.

Glia and Central Sensitization

Accumulating evidence suggests that dorsal horn glia cells might have an important role in producing and maintaining abnormal pain sensitivity.^57,58 Synapses within the CNS are encapsulated by glia that do not normally respond to nociceptive input from local sites. Following the initiation of central sensitization, however, spinal glia cells are activated by a wide array of factors that contribute to hyperalgesia, such as immune activation within the spinal cord, SP, excitatory amino acids, nitric oxide, and prostaglandins. Once activated, glia cells release proinflammatory cytokines, including tumor necrosis factor, IL-6 and IL-1, SP, nitric oxide, prostaglandins, excitatory amino acids, ATP, and fractalkine⁵⁹ that, in turn, further increase the discharge of excitatory amino acids and SP from the Ab and C afferents that synapse in the dorsal horn and also enhance the hyperexcitability of the dorsal horn neurons.^57,60 Recent evidence also points toward a possible role for NMDA receptors in glial activation and pain.⁶¹

Factors Related to Central Sensitization

As a normal response to tissue trauma, injury is followed by repair and healing. Inflammation occurs, which results in a cascade of electrophysiological and chemical events that resolve over time and the patient becomes pain free. In persistent pain, however, the local, spinal, and even supraspinal responses are considerably different from those that occur during acute pain. While defining the relationship between tissue events and pain is necessary for understanding the clinical context of these pathologies, defining the relationship between injury and specific and relevant nociceptive responses is crucial for understanding the central mechanisms of persistent pain in fibromyalgia. It must be emphasized however, that specific abnormalities in persons with fibromyalgia that might produce the prolonged impulse input that is necessary to initiate the events underlying the development of central sensitization and/or spinal glia cell activation have not been identified. After central sensitization has occurred, low threshold Aβ afferents, which normally do not serve to transmit a pain response, are recruited to transmit spontaneous and movement-induced pain. This central hyperexcitability is characterized by WU responses of repetitive C fiber stimulation, expanding receptive field areas, and spinal neurons taking on properties of wide dynamic range neurons.⁶² Ultimately, Aβ fibers stimulate postsynaptic neurons to transmit pain, where these Aβ fibers previously had no role in pain transmission, all leading to central sensitization. Nociceptive information is transmitted from the spinal cord to supraspinal sites, such as the thalamus and cerebral cortex, by ascending pathways.

Conclusion

Fibromyalgia is a chronic pain syndrome that is characterized by widespread pain in peripheral tissues, psychological distress, and central sensitization. Whereas the role of psychological factors for fibromyalgia patients’ pain has been well established, little is known about the origin of the sensory abnormalities for pain. Deep tissue impulse input is most likely relevant for the initiation and/or maintenance of abnormal central pain processing and represents an important target for new treatments of this chronic pain syndrome.^39,63 In addition to well-established central pain processing abnormalities, peripheral impulse input likely plays an important role for chronic pain in fibromyalgia. Despite limited trial experience three important strategies for fibromyalgia therapy appear useful at this time: first, improvement or prevention of central sensitization; second, reduction of peripheral nociceptive input, particularly from muscles; and third, treatment of negative affect, particularly depression. Reduction of peripheral input is most likely relevant for acute fibromyalgia pain exacerbations and includes physical therapy, muscle relaxants, muscle injections, and anti-inflammatory analgesics. Central sensitization can be successfully ameliorated by cognitive-behavioral therapy, sleep improvement, neurokinin antagonists, NMDA receptor antagonists, and anti-seizure medications. The pharmacologic and behavioral treatment of secondary pain affect (anxiety, anger, depression) and unrefreshing sleep is equally important and represent some of the most powerful interventions for fibromyalgia pain. The co-aggregation of fibromyalgia with MDD in family studies suggests a shared role of biogenic amines for both illnesses.⁶⁴ Antidepressants, particularly combined serotonin norepinephrine reuptake inhibitors (SNRIs), seem to be efficacious for fibromyalgia pain in several clinical trials.⁶⁵ However, until now, no antidepressant therapy has received Food and Drug Administration approval for the treatment of fibromyalgia pain. Pregabalin (α2δ ligand) has been indicated for fibromyalgia by the FDA and several balanced SNRIs are likely to follow. Whether narcotics are useful for the treatment of fibromyalgia pain is unknown at this time because of insufficient trial experience.

References

1.   Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994;37(11):1593-1601.
2.   Bradley LA, Alarcon GS, Sotolongo A, et al. Cerebrospinal fluid (CSF) levels of substance P (SP) are abnormal in patients with fibromyalgia (FM) regardless of traumatic or insidious pain onset. Arthritis Rheum. 1998;41:256.
3.   Vaeroy H, Helle R, Forre O, Kass E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988;32(1):21-26.
4.   Neeck G. Neuroendocrine and hormonal perturbations and relations to the serotonergic system in fibromyalgia patients. Scand J Rheumatol Suppl. 2000;113:8-12.
5.   Lautenschlager J, Bruckle W, Schnorrenberger CC, Muller W. [Measuring pressure pain of tendons and muscles in healthy probands and patients with generalized tendomyopathy (fibromyalgia syndrome)]. Z Rheumatol. 1988;47(6):397-404.
6.   Quimby LG, Block SR, Gratwick GM. Fibromyalgia: generalized pain intolerance and manifold symptom reporting. J Rheumatol. 1988;15(8):1264-1270.
7.   Tunks E, Crook J, Norman G, Kalaher S. Tender points in fibromyalgia. Pain. 1988;34(1):11-19.
8.   Mikkelsson M, Latikka P, Kautiainen H, Isomeri R, Isomaki H. Muscle and bone pressure pain threshold and pain tolerance in fibromyalgia patients and controls. Arch Phys Med Rehabil. 1992;73(9):814-818.
9.   Kosek E, Ekholm J, Hansson P. Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue. Pain. 1995;63(3):335-339.
10. Crofford LJ, Young EA, Engleberg NC, et al. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun. 2004;18(4):314-325.
11. Crofford LJ. The hypothalamic-pituitary-adrenal axis in fibromyalgia: Where are we in 2001? J Musculoskelet Pain. 2002;10:215-220.
12. Bradley LA, Sotolongo A, Alberts KR, et al. Abnormal regional cerebral blood flow in the caudate nucleus among fibromyalgia patients and non-patients is associated with insidious symptom onset. J Musculoskelet Pain. 1999;7:285-292.
13. Larson AA, Giovengo SL, Russell IJ, Michalek JE. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain. 2000;87(2):201-211.
14. Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999;26(7):1564-1569.
15. Welin M, Bragee B, Nyberg F, Kristiansson M. Elevated substance P levels are contrasted by a decrease in met-enkephalin-arg-phe levels in CSF from fibromyalgia patients. J Musculoskelet Pain. 1995;3(suppl):4.
16. Bradley LA, Alberts KR, Alarcon GS, et al. Abnormal brain regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) levels of substance P (SP) in patients and non-patients with fibromyalgia (FM). Arthritis Rheum. 1996;39(suppl 19):212.
17. Russell IJ. Advances in fibromyalgia: possible role for central neurochemicals. Am J Med Sci. 1998;315(6):377-384.
18. Almay BG, Johansson F, Von-Knorring L, Le-Greves P, Terenius L. Substance P in CSF of patients with chronic pain syndromes. Pain. 1988;33(1):3-9.
19. Fischer HP, Eich W, Russell IJ. A possible role for saliva as a diagnostic fluid in patients with chronic pain. Semin Arthritis Rheum. 1998;27(6):348-359.
20. Sjostrom S, Tamsen A, Hartvig P, Folkesson R, Terenius L. Cerebrospinal fluid concentrations of substance P and (met)enkephalin-Arg6-Phe7 during surgery and patient-controlled analgesia. Anesth Analg. 1988;67(10):976-981.
21. Murphy RM, Zemlan FP. Differential effects of substance P on serotonin-modulated spinal nociceptive reflexes. Psychopharmacol (Berl). 1987;93(1):118-121.
22. Schwarz MJ, Späth M, Müller-Bardorff H, Pongratz DE, Bondy B, Ackenheil M. Relationship of substance P, 5-hydroxyindole acetic acid and tryptophan in serum of fibromyalgia patients. Neurosci Lett. 1999;259(3):196-198.
23. Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999;26(7):1564-1569.
24. Crofford LJ, Engleberg NC, Demitrack MA. Neurohormonal perturbations in fibromyalgia. Baillieres Clin Rheumatol. 1996;10(2):365-378.
25. Crofford LJ, Pillemer SR, Kalogeras KT, et al. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum. 1994;37(11):1583-1592.
26. Neeck G, Crofford LJ. Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin North Am. 2000;26(4):989-1002.
27. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25(1):1-35.
28. Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: A pilot study in fibromyalgia. Arthritis Rheum. 2000;43(4):872-880.
29. McLean SA, Williams DA, Stein PK, et al. Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia. Neuropsychopharmacology. 2006;31(12):2776-2782.
30. Fuller RW. The involvement of serotonin in regulation of pituitary-adrenocortical function. Front Neuroendocrinol. 1992;13(3):250-270.
31. Fuller RW. Serotonin receptors involved in regulation of pituitary-adrenocortical function in rats. Behav Brain Res. 1996;73(1-2):215-219.
32. Simms RW. Fibromyalgia is not a muscle disorder. Am J Med Sci. 1998;315:346-350.
33. Sprott H, Bradley LA, Oh SJ, et al. Immunohistochemical and molecular studies of serotonin, substance P, galanin, pituitary adenylyl cyclase-activating polypeptide, and secretoneurin in fibromyalgic muscle tissue. Arthritis Rheum. 1998;41(9):1689-1694.
34. Sprott H, Salemi S, Gay RE et al. Increased DNA fragmentation and ultrastructural changes in fibromyalgic muscle fibres. Ann Rheum Dis. 2004;63(3):245-251.
35. Salemi S, Rethage J, Wollina U, et al. Detection of interleukin 1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol. 2003;30(1):146-150.
36. McIver KL, Evans C, Kraus RM, Ispas L, Sciotti VM, Hickner RC. NO-mediated alterations in skeletal muscle nutritive blood flow and lactate metabolism in fibromyalgia. Pain. 2006;120(1-2):161-169.
37. Graven-Nielsen T, Arendt-Nielsen L. Is there a relation between intramuscular hypoperfusion and chronic muscle pain? J Pain. 2002;3(4):261-263.
38. Elvin A, Siosteen AK, Nilsson A, Kosek E. Decreased muscle blood flow in fibromyalgia patients during standardised muscle exercise: A contrast media enhanced colour Doppler study. Eur J Pain. 2006;10(2):137-144.
39. Staud R, Vierck CJ, Robinson ME, Price DD. Overall fibromyalgia pain is predicted by ratings of local pain and pain related negative affect: possible role of peripheral tissues. Rheumatology (Oxford). 2006;45(11):1409-1415.
40. Forseth KO, Forre O, Gran JT. A 5.5 year prospective study of self-reported musculoskeletal pain and of fibromyalgia in a female population: significance and natural history. Clin Rheumatol. 1999;18(2):114-121.
41. McBeth J, Macfarlane GJ, Benjamin S, Silman AJ. Features of somatization predict the onset of chronic widespread pain: results of a large population-based study. Arthritis Rheum. 2001;44(4):940-946.
42. Arnold LM, Hudson JI, Hess EV, et al. Family study of fibromyalgia. Arthritis Rheum. 2004;50(3):944-952.
43. Thieme K, Turk DC, Flor H. Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Psychosom Med. 2004;66(6):837-844.
44. Raphael KG, Janal MN, Nayak S, Schwartz JE, Gallagher RM. Familial aggregation of depression in fibromyalgia: a community-based test of alternate hypotheses. Pain. 2004;110(1-2):449-460.
45. Woolf CJ. Windup and central sensitization are not equivalent. Pain. 1996;66(2-3):105-108.
46. Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain. 1999;79(1):75-82.
47. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46(5):1333-1343.
48. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. 2001;91(1-2):165-175.
49. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology. 1987;26:1235-1238.
50. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci USA. 1999;96(14):7723-7730.
51. Staud R, Domingo M. Evidence for abnormal pain processing in fibromyalgia syndrome. Pain Med. 2001;2(3):208-215.
52. Staud R, Domingo M. New Insights into the pathogenesis of fibromyalgia syndrome. Med Aspects Hum Sex. 2001;1:51-57.
53. Vierck CJ, Staud R, Price DD, et al. The effect of maximal exercise on temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. J Pain. 2001;2(6):334-344.
54. Staud R. Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Curr Rheumatol Rep. 2002;4(4):299-305.
55. Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain. 2002;99(1-2):49-59.
56. Staud R, Robinson ME, Vierck CJ Jr, Cannon RC, Mauderli AP, Price DD. Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome. Pain. 2003;105(1-2):215-222.
57. Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001;24(8):450-455.
58. Wieseler-Frank J, Maier SF, Watkins LR. Glial activation and pathological pain. Neurochem Int. 2004;45:389-395.
59. Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals. 2005;14(4):166-174.
60. Watkins LR, Maier SF. When good pain turns bad. Curr Dir Psychol Sci. 2003;12(6):232-236.
61. Salter MW. Cellular signalling pathways of spinal pain neuroplasticity as targets for analgesic development. Curr Top Med Chem. 2005;5:557-567.
62. Cook AJ, Woolf CJ, Wall PD, McMahon SB. Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature. 1987;325(7000):151-153.
63. Vierck CJ, Jr. Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia). Pain. 2006;124(3):242-263.
64. Bazzichi L, Giannaccini G, Betti L et al. Alteration of serotonin transporter density and activity in fibromyalgia. Arthritis Res Ther. 2006;8(4):R99.
65. Delgado PL. Serotonin noradrenaline reuptake inhibitors: New hope for the treatment of chronic pain. Int J Psychiatr Clin Pract. 2006;10:16-21.