Open access peer-reviewed chapter

Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia

Written By

Vishwas Tripathi, Amaresh Mishra, Yamini Pathak, Aklank Jain and Hridayesh Prakash

Submitted: 14 August 2020 Reviewed: 14 October 2020 Published: 30 October 2020

DOI: 10.5772/intechopen.94492

From the Edited Volume


Edited by Hridayesh Prakash

Chapter metrics overview

1,008 Chapter Downloads

View Full Metrics


Fibromyalgia (FM) or Fibromyalgia Syndrome (FMS) is a neurodegenerative disorder causing musculoskeletal pain, tenderness, stiffness, fatigue, and sleep disorder in the body. It is one of the most common chronic pain conditions, affecting about 6% of the world population. Being refractory, till date, no specific treatment of this disease is available. Accumulating evidences over the last few decades indicate that proinflammatory macrophages, cytokines, & chemokines as the key players in this disease. Recent findings suggest activation of Microglial cells and associated pro-inflammatory signals as one of the major causes of chronic pain in patients suffering from fibromyalgia. Increased density of iNOs/CD68+ M1 effector macrophages has been associated with neuropathic pain models. In light of this, depletion of these pro-inflammatory macrophages has been shown to reduce sensitivity to neuropathic pain. On the other hand, modulating pattern of AGEs (Advanced Glycation End-Products) can also contribute to inactivation of macrophages. These findings strongly suggest that macrophages are critical in both inflammatory and neuropathic pain. Therefore, this chapter highlights the impact of macrophage plasticity in various immunopathological aspects of fibromyalgia.


  • fibromyalgia
  • Th1/Th2 immune response
  • M1/M2 macrophages
  • neurodegeneration

1. Introduction

Fibromyalgia has been considered a rheumatologic disease, also known as fibrositis and myofascial pain syndrome. Fibromyalgia affects the muscles, ligaments & tendons, and bones with no signs of inflammation of the tissue [1]. The origin of fibromyalgia is still not clear, although several hypotheses stated fibromyalgia condition associated with depression and brain-based neuronal dysfunctions i.e. coaxially linked with non-uniform signal transduction mechanism. Preclinical studies addressing the symptoms of fibromyalgia are increased levels of substance P (SP) in the cerebrospinal fluid (CSF) of the individuals. SP is a peptide which is composed of 11 amino acids and acts as a neurotransmitter. It plays a significant role in pain stimulations from the peripheral nervous system to the central nervous system [2]. Fibromyalgia patients showed a 3-fold increase in the levels of substance P in CSF which possibly activates neurokinin (NK) receptors that induce chronic pain [34]. Moreover, besides NK receptors, the excitation of amino acid receptors such as N-methyl D-aspartate (NMDA) receptors also leads to hyperalgesia in fibromyalgia [5]. This is associated with the deficiency of Dopamine during chronic pain in fibromyalgia [6]. It is a neurotransmitter of the Central nervous system (CNS) and regulates the pain processing of CNS. On the other hand, several studies indicating that macrophages, cytokines/chemokines, and oxidative stress are the key mediator of immune activation and inflammation in fibromyalgia condition [7].

Nitric oxide (NO), is a principal determinant of normal endothelial and vascular function. During inflammatory reactions, NO production increases considerably and, contributes to oxidative stress together with other reactive oxygen species (ROS) [8]. Macrophages that have a pro-inflammatory role are called classically-activated (M1) macrophages. Classically-activated (M1) macrophages are activated by Lipopolysaccharide (LPS) and Interferon-gamma (IFN-γ). The role of activated M1 macrophages is to secrete pro-inflammatory cytokines and chemokines and present antigens [9, 10]. Cytokines produced by T helper type 1 (Th1) cells, induce the differentiation of classically activated (M1) macrophages [11, 12]. Some of the pro-inflammatory cytokines including TNF-α, IL-1, IL-6, and IL-8 have been reportedly linked with the immunopathology of fibromyalgia. Prolonged activation of M1 macrophages has been reported to encourage neuro-inflammation which may responsible for the pathogenesis of neuropathic pain among the fibromyalgia patients [13, 14, 15]. There is no successful medication yet that has been proven to treat fibromyalgia completely.

1.1 Epidemiology

Fibromyalgia prevalence is more common among women as compared to men and risk increases significantly after growing age [16]. Apparently, in population studies indicate that there is a need for a standardized gender-based diagnostic approach that can allow for more reliable diagnosis and some of the gender biases that relate to women suffering the most. It is estimated globally that there is about 6% of the patient that suffers from this chronic disease out of which 68 percent are females [17]. Patients who need tertiary care pain clinic help, more than 40% outcome measure is a resolution of symptoms of fibromyalgia [18]. Patients with existent chronic rheumatic diseases are having high risk of fibromyalgia (Figure 1).

Figure 1.

Reason of high prevalence rate of fibromyalgia among women.

1.2 Etiology and pathophysiology

Fibromyalgia is a chronic pain disorder but the etiology of the disease still not clear [19, 20]. Fibromyalgia is triggered by multiple physical and/or emotional stress factors. There is increasing evidence that revealed the role of macrophages including activated M1 macrophages, and inducible nitric oxide synthase (iNOS) in pain conditions in fibromyalgia [21]. Significantly, macrophages can mediate microglial activation through the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [22]. In addition, levels of pro-inflammatory cytokines and chemokines are enhanced in serum and could contribute to inflammation at the systemic level. On the other hand, alteration of central nervous system (CNS) cells occurs in fibromyalgia cause discomfort and sensory perception [5]. The functional neuroimaging technique rests crucially on the identification of pain-sensitive areas in regions of the Brain. Furthermore, differences in activation of pain-sensitive areas of the brain by functional neuroimaging techniques have been revealed in fibromyalgia condition. Several pharmacological studies have shown a genetic predisposition for fibromyalgia though there is no documentation of a definitive candidate gene [23]. About one-third of fibromyalgia patients have a close relative with rheumatic disease/fibromyalgia history (Figure 2) [24].

Figure 2.

Progression and diagnosis process of fibromyalgia.

1.2.1 Psychological stress and trauma

Research has also shown that stress is linked with the increasing risk of developing fibromyalgia [25]. Psychologic factors including stress, trauma, anxiety, and depression have been shown their role in pain severity in fibromyalgia patients [26, 27]. Corticotrophin-releasing hormone (CRH), is a well-known hormone for stress response mediators, was found high in the cerebrospinal fluid (CSF) among fibromyalgia patients and was linked with pain [28]. Fibromyalgiais quite common in individuals with mastocytosis [29] where mast cells influence the infiltration, in situ differentiation and inflammatory response of macrophages and neutrophils; in various organs. This type of rapid proliferation of mast cells causes itchy bumps on the skin, diarrhea, and bone pain. Emotional stress is the primary symptom among the individuals suffering from mastocytosis and reportedly found high serum levels of CRH in mastocytosis patients [30]. CRH, nerve growth factor, neurotensin and substance P are known as stress peptides which released in peripheral tissues like blood vessels, muscles, and skin during allergic, immune, and stress reaction in the body. In another study, upregulation of nerve growth factor in the CSF among the patients suffering from fibromyalgia [31] and has been considered as a target for analgesic therapy [32].

1.2.2 Neuro-inflammation

A correlation between macrophages and mast cells (MCs) has been revealed in fibromyalgia [33, 34]. Numerous studies suggested macrophages and MCs play a key role during the pain and inflammation [35, 36, 37, 38]. Macrophages and MCs also release pro-inflammatory and neuro-sensitizing molecules such as cytokines and chemokines which act as modulators of nociception, and elevated pain sensitivity through their receptors [39, 40, 41]. In addition, a growing body of evidence indicated the increased levels of the pro-inflammatory chemokines in both serum and CSF of fibromyalgia patients [42, 43, 44]. CSF and IL-17 are also associated with pain, depression, and anxiety which are the key symptoms among the individuals suffering from fibromyalgia [45, 46].

1.2.3 Central sensitization

By far the most important thing to understand about the pain and fatigue induced by fibromyalgia is central pain sensitization. Many nociceptive dorsal root ganglion (DRG) neurons express pro-inflammatory cytokine and chemokine receptors that are upregulated after nerve injury [47]. Long-lasting neuro-inflammation through the upregulation of inflammatory molecules can contribute to the ectopic discharge of sensory neurons, resulting in peripheral sensitization. Prolonged abnormal transmission of pain signaling due to peripheral sensitization triggers central sensitization [48, 49, 50], mediated by pain-processing neurons and activation of glial cells (Figure 3) [51, 52, 53, 54]. Glial cells are activated by various neurotransmitters, such as cytokines, chemokines, and nucleotides and these activated glial cells directly or indirectly involved in central sensitization [10, 55, 56, 57, 58]. Moreover, these cells can contribute to brain inflammation and pathogenesis of different brain disorders [59, 60, 61, 62, 63, 64, 65].

Figure 3.

Contribution of macrophage derived inflammatory response in neuropathic pain in peripheral nervous system.

1.2.4 Fascia

It has been hypothesized that inflammation of fascia is a secondary source of the increased pain transmitting to the spinal cord. Fascia is the thick connective tissue surrounding the cells of the muscles etc. The fascial system covers every part of a muscle and is a thick gel of ground material that suspends muscle cells and fibers [66]. Additionally, muscle innervation is found primarily in the fascia, hence the fascia is highly susceptible. Muscle biopsy, cell studies of FM patients result in higher levels of collagen and symptoms of oxidative stress and tissue damage, indicating fascial inflammation. Although findings were not consistent in considering the hypothesis of fascial inflammation as the fibromyalgia etiology [67]. Conversely, these inflammations may be due to low growth hormone production and HPA axis dysfunction, resulting in increased nociception, central sensitization, and chronic pain [68].

1.2.5 Altered biochemistry

Substance P (SP) is an 11-amino acid peptide IS primarily responsible in the neurotransmission of pain to the central nervous system (CNS). Substance P (SP) is associated with chronic pain found to be elevated with fibromyalgia in the cerebral spinal fluid (CSF) compared to controls [4, 5]. However, the diagnostic study also revealed low neurotransmitter levels involved in regulating sensory perception and also inhibit pain transmission, such as serotonin, norepinephrine, and dopamine, etc.

1.2.6 Nitric oxide synthase (NOS)

Fibromyalgia patients have higher oxidative stress index and lower total nitrite levels than healthy controls [69, 70]. NO plays a crucial role in chronic pain states with cyclooxygenase-2 (COX-2) as termed in central sensitization [71]. Numerous studies considered NO as an important neurotransmitter involved in the pain and sensitization pathways related to NOS activation. Therefore, the NO can actively participate in the hyper sensitization in patients with fibromyalgia. The NO is synthesized by the nitric oxide synthase (NOS) enzyme which has four isoforms i.e. neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), mitochondrial nitric oxide synthase (mtNOS), and inducible nitric oxide synthase (iNOS) [72, 73]. The nNOS, eNOS, and mtNOS are expressed in the majority of the cells. The nNOS and eNOS are regulated by Ca2+ fluxes, whereas iNOS is regulated by cytokines. iNOS is expressed only in response to some pathological stimuli typically bypro-inflammatory cytokines and/or bacterial lipopolysaccharide (LPS) [74, 75]. Inducible nitric oxide synthase (iNOS) together with oxidative stress plays an important role in the development of vascular dysfunction in sepsis. In fibromyalgia, a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) [8]. Various studies have revealed the iNOS role in the development of inflammatory and neuropathic pain including fibromyalgia. Nitric oxide (NO) has various physiological functions such as vasodilation, muscle relaxation, learning, memory, neurotransmission, several degenerative processes and inflammation [8]. Copious amount of NO production is critical for the inflammatory response and the innate immune system. Overexpression or dysregulation of iNOS is linked with local inflammatory reactions and contributed to various human diseases [75, 76]. Considering this, iNOS inhibitory therapeutics could be promising for the treatment of neurodegenerative pain including fibromyalgia.


2. Role of activated macrophages/myeloid cells in the neuromyalgia

In turn, mast cells interplay with microglia, which are the resident macrophages of the central nervous system that may contribute to increased inflammation through the secretion of cytokines [59, 77]. The cytoplasmic receptor Nod-like receptor-2 (NOD2), and its adaptor-signaling molecule RIPK2, have been shown to be involved in the development of neuropathic pain after peripheral nerve injury. The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of a wide of pro-nociceptive cytokines. The studies strongly suggest the undetermined significance of NOD2 signaling in the development of neuropathic pain and to highlight potential new means of the target for preventing neuropathic pain [78]. Macrophages are important participants in regulating neuro- inflammation (Figure 4); consequently, they are considered to be a common peripheral regulator of neuropathic pain [79, 80, 81].

Figure 4.

Pathogenic role of Th1 primed (iNOS+) macrophages and mast cells during progression of fibromyalgia.


3. Current therapies

There is no effective therapeutic approach available for fibromyalgia, but many drugs have been available to reduce its symptoms and pain. Patients suffering from fibromyalgia should integrate pharmacologic therapy with non-pharmacologic therapies [82]. In a study, it has been revealed that multi-component treatment could be effective in the short term for improving key symptoms of fibromyalgia including pain, fatigue, depression, and quality of life [83]. Modern medicine has most certainly come a long way in providing relief from the conditions and diseases of the day, sometimes other options can be just as helpful, if not more beneficial, in providing relief of fibromyalgia symptoms. Moreover, the prescription medications that are commonly used for the treatment of fibromyalgia symptoms can cause negative side effects that the individual must then deal with in addition to the problems along with symptoms of fibromyalgia. In order to regulate inflammation, role of macrophages is very crucial. As we described previously also, macrophages are important to sense damage to the tissue and initiate the recruitment of circulating leukocytes through triggering the chemokines secretion. The direct physical interaction stimulates production of reactive oxygen species (ROS) at the site of the injury. At the late stages of muscle regeneration, macrophages refrain the expression of both pro-inflammatory and anti-inflammatory cytokines and turned to a silenced mode. Conversely, interleukin 4 (IL-4) actions are considered to be regulated by the inhibition of pro inflammatory mediators. In a study, IL-4 blood levels were found reduced among the patients suffering with chronic widespread pain including fibromyalgia when compared with controls [84, 85]. Several study indicating that the endogenous opioid system is essential to the actions of IL-4 and M2 macrophages in pain control [21]. Concluding this, macrophages play a central role in the regulation of inflammation from the beginning to the end. This is a timely area of research to explore the role of macrophages particularly M2 macrophages which sounds more promising for tackling pathological pain.

However, there are some alternative therapeutic approaches to fibromyalgia that have been proven by research to aid in providing relief from its symptoms (Figure 5).

Figure 5.

Effective alternative therapeutic approaches suggested for fibromyalgia patients.

3.1 Non-pharmacologic therapy

Patients diagnosed with fibromyalgia must know their illness before starting their medications [86, 87, 88]. It was found that educational intervention had significantly better improvement among fibromyalgia patients [82]. In another study, fibromyalgia patients reduce the fear of pain and fear of disease complications using cognitive behavioral therapy [83]. Cardio exercise is suggested for fibromyalgia patients as it helps to improve the sleep and reduce the pain as well [89, 90]. In a study, they uses Chinese stress reduction exercise programs and improvement reported among the fibromyalgia patients to reduce the key symptoms of fibromyalgia [91, 92]. Nutritional supplementation is often used in fibromyalgia, but the objective findings are limited [93, 94]. Coenzyme Q₁₀supplementation in fibromyalgia patients improved the disease symptoms as it reduces the oxidative damage that leads to muscle fatigue [95, 96]. Another study revealed that500mg L-carnitine for 20 days has significant benefits to fibromyalgia patients which lasts up to 10 weeks [97]. Natural flavonoids like quercetin and luteolin giving promising results to reduce the key symptoms of fibromyalgia due to its anti-inflammatory, antioxidant, and anti-allergic property [98, 99, 100, 101]. Moreover, flavonoids have been discussed as a possible treatment of central nervous system disorders [102, 103].

3.2 Pharmacologic therapy

There’s no complete cure available for fibromyalgia, but there are many medicines available to treat fibromyalgia symptoms. Some drugs ease aches, fatigue, and pains, while others may boost your energy or improve your sleep. Fibromyalgia drugs mainly target pain modulatory mechanisms. There is an urgent need to develop new drugs targeting the fibromyalgia mechanism and treat its symptoms (Table 1).

S.N.Drug typeDrugs nameEffects on fibromyalgiaSide-effectsReferences
1.AntidepressantsAmitriptyline Citalopram,Escitalopram, Fluvoxamine, Fluoxetine, Paroxetine, SertralineImprovement in pain, fatigue, and sleepDrowsiness, Weight gain, Nausea fatigue, Dry mouth, Blurred vision, Constipation, Dizziness, and Change in appetite[104, 105, 106, 107]
2.Anti-Seizure MedicinesPregabalin, GabapentinImprovement in pain, fatigue, and sleepBlurry vision, dizziness, Drowsiness, Weight gain, and Swelling of hands/feet[18, 28, 83, 87, 104, 108, 109, 110, 111]
3.Pain Relieversacetaminophen and Non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen, naproxen, and tramadolImprovement in aches and painsHeart attack, Stroke ulcers & bleeding in the stomach, Intestines liver damage, Stomach pain, Constipation, Nausea, and Trouble concentrating[112]
4.Muscle RelaxantsCyclobenzaprine (Flexeril) Tizanidine (Zanaflex)Improvement in pain, fatigue, and sleepDry mouth, Dizziness, Blurry vision, Headaches, Chest pain, Nausea, and Fever[113]
5.Serotonin inhibitorsDuloxetine, Milnacipran, Reboxetine, Esreboxetine, Citalopram, escitalopram, fluoxetine, paroxetineImprovement in pain, and depressionDifficulty in sleeping, Headaches, Dizziness, Blurry vision,Constipation/diarrhea, Nausea/vomiting, Dry mouth, and sweating[104, 105, 114, 115, 116, 117, 118, 119, 120, 121]
6.GabapentinoidPregabalin, gabapentin, LacosamideImprovement in pain, fatigue, and sleepAbnormal eye movements (continuous, & uncontrolled, rolling), Clumsiness, Constipation/diarrhea, Difficulty speaking, Tiredness, Dry mouth, and Nausea.[93, 104, 105, 109, 121, 122, 123, 124]
7.CannabinoidNabilone, DronabinolImprovement in pain, fatigue, anxiety, and sleep.Dizziness, Drowsiness, Dry mouth, Feeling “high,” Lightheadedness, Headache, and Insomnia[125, 126, 127, 128]
8.NMDA antagonistKetamineImprovement in painHigh/Low blood pressure, Increased cardiac output, Visual hallucinations, Vivid dreams, and Double vision[129, 130, 131, 132]
9.Nitrogen-containing bases inhibitorsMethotrexate, Azathioprine, LeflunomideImprovement in painDizziness, Headache, Tender gums, Decreased appetite, Reddened Eyes, and Hair Loss[133]
10.Tumor Necrosis Factor (TNF) inhibitorsHydroxychloroquine, Adalimumab, Golimumab, Certolizumab, Infliximab, Sulfasalzine and EtanerceptImprovement in pain, and fatigueSwelling, Redness or itchy skin where your injection was given, A mild nose, throat or sinus infection,Headache, Stomach pain, and Dizziness[134, 135]

Table 1.

Available pharmacological interventions for fibromyalgia.


4. Immune mediated therapeutic interventions

It is a well-established concept that the immune system plays a crucial role in various chronic pain conditions including fibromyalgia. The immune system involves the release of autoantibodies, pro-inflammatory cytokines, chemokines, substance P, histamine, tumor necrosis factor, interleukins, and prostaglandins [9]. In a study, IL-8 level elevated in the serum of patients suffering from fibromyalgia confirming the relation between fibromyalgia and higher levels of pro-inflammatory cytokines [136]. In another study, the role of the NLRP3 inflammasome in fibromyalgia patients along with animal models was investigated. In the outcome of the same study, it has been revealed that increased levels of IL-1b were positively linked with pain in both mice and fibromyalgia patients [137]. This was the first of its kind study to show the relation between inflammasome and increased pro-inflammatory cytokines among the fibromyalgia patients which confirm the direct link between inflammation and pain. Naltrexone and naloxoneisan antagonist of mu-opioid receptors and both were effective to inhibit cytokine expression [138139]. Using neuron–glia co-cultures pre-treated with naloxone and subsequently treated with LPS, it was demonstrated that naloxone protects against lipopolysaccharide (LPS)-induced neurotoxicity through the inhibition of the proinflammatory factors and free radicals [139]. Similarly, naltrexone also blocked LPS-induced inflammation and microglial activity and inhibited TNF-α production [139, 140]. Due to the promising preclinical data, clinical trial was conducted for the naltrexone and it has been found that it effectively reduced the key disease symptoms among the fibromyalgia patients [141]. Observational studies provide evidence that vagus nerve activation can down-regulated inflammation through nAChR-mediated inhibition of macrophage function [142, 143, 144, 145]. Treatment with nicotine can inhibit the development of inflammatory cytokines release by LPS-stimulated macrophages through the activation of α7 nAChR signaling [143, 144, 146, 147, 148]. Following this, anti-inflammatory treatments could be promising in the therapeutics in fibromyalgia condition.


5. Conclusion

Fibromyalgia condition is defined by widespread musculoskeletal pain followed by fatigue, sleep, depression, and anxiety. The available allopathic medicines have their limitations and side effects and to date no permanent treatment of fibromyalgia is available. However, research is going on to find out more alternative options that can be used for treating various chronic conditions. Hence the need of the hour is to explore various alternative therapies for this condition. Despite various research and findings on fibromyalgia, it is found by most of the scientist that this disease is characterized by the abnormal nerve to signal transduction thus “the hypothesis of pain in the brain” is proven here and therefore effective neuronal diagnosis should be conducted before designing the treatment protocols. Thus, the emphasis of treatment must be in-combat with the brain to muscle co-ordinations. It has been well established that the immune system is an important part and plays a key role in the complex pathogenesis of fibromyalgia. Macrophages, inflammatory cytokines, and reactive oxygen species play distinct roles in the inflammatory response. Inducible nitric oxide synthase (iNOS) dysregulation is implicated in a variety of chronic and acute diseases and inhibitors of iNOS show noteworthy results in animal models for septic shock, pain, and other conditions, but failed in clinical trials. Conversely, macrophages play a crucial role to regulate peripheral sensitization, cytokines, and chemokines derived from these cells and are potential novel therapeutic targets. Few studies were conducted in order to explore macrophage therapeutics in the animal model and have been shown to prevent/relieve neuropathic pain, but their efficacy has not yet been evaluated in clinical trials. To move evidence-based interventions into practice, pharmacotherapies that target macrophage-driven neuro-inflammation will undoubtedly open up new avenues for beneficial treatment of intractable neuropathic pain.

Concluding this, further research is required to clarify the role of inflammation and the mechanisms that regulate neuropathic pain in fibromyalgia as well as to shed light on potential therapeutic options.


  1. 1. Fischer AA. New developments in diagnosis of myofascial pain and fibromyalgia. Physical Medicine and Rehabilitation Clinics of North America. 1997
  2. 2. Zieglgänsberger W. Substance P and pain chronicity. Cell and Tissue Research. 2019
  3. 3. Liu Z, Welin M, Bragee B, Nyberg F. A high-recovery extraction procedure for quantitative analysis of substance P and opioid peptides in human cerebrospinal fluid. Peptides. 2000;
  4. 4. Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, et al. Elevated cerebrospinal fluid levels of substance p in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994;
  5. 5. Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic widespread pain. Neuroscience. 2016
  6. 6. Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA, et al. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci. 2007;
  7. 7. Coskun Benlidayi I. Role of inflammation in the pathogenesis and treatment of fibromyalgia. Rheumatology International. 2019
  8. 8. Lubos E, Handy DE, Loscalzo J. Role of oxidative stress and nitric oxide in atherothrombosis. Frontiers in Bioscience. 2008
  9. 9. Duque GA, Descoteaux A. Macrophage cytokines: Involvement in immunity and infectious diseases. Frontiers in Immunology. 2014
  10. 10. Totsch SK, Sorge RE. Immune system involvement in specific pain conditions. Molecular Pain. 2017
  11. 11. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nature Immunology. 2010
  12. 12. Sica A, Mantovani A. Macrophage plasticity and polarization: In vivo veritas. Journal of Clinical Investigation. 2012
  13. 13. Kiguchi N, Kobayashi Y, Saika F, Sakaguchi H, Maeda T, Kishioka S. Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain. 2015;
  14. 14. Kiguchi N, Sakaguchi H, Kadowaki Y, Saika F, Fukazawa Y, Matsuzaki S, et al. Peripheral administration of interleukin-13 reverses inflammatory macrophage and tactile allodynia in mice with partial sciatic nerve ligation. J Pharmacol Sci. 2017;
  15. 15. Komori T, Morikawa Y, Inada T, Hisaoka T, Senba E. Site-specific subtypes of macrophages recruited after peripheral nerve injury. Neuroreport. 2011;
  16. 16. Arout CA, Sofuoglu M, Bastian LA, Rosenheck RA. Gender Differences in the Prevalence of Fibromyalgia and in Concomitant Medical and Psychiatric Disorders: A National Veterans Health Administration Study. J Women’s Heal. 2018;
  17. 17. Goldenberg DL, Bradley LA, Arnold LM, Glass JM, Clauw DJ. Understanding fibromyalgia and its related disorders. In: Primary Care Companion to the Journal of Clinical Psychiatry. 2008
  18. 18. Brill S, Ablin JN, Goor-Aryeh I, Hyat K, Slefer A, Buskila D. Prevalence of fibromyalgia syndrome in patients referred to a tertiary pain clinic. J Investig Med. 2012;
  19. 19. Sarzi-Puttini P, Atzeni F, Mease PJ. Chronic widespread pain: From peripheral to central evolution. Best Practice and Research: Clinical Rheumatology. 2011
  20. 20. Schmidt-Wilcke T, Clauw DJ. Fibromyalgia: From pathophysiology to therapy. Nature Reviews Rheumatology. 2011
  21. 21. Celik M, Labuz D, Keye J, Glauben R, Machelska H. IL-4 induces M2 macrophages to produce sustained analgesia via opioids. JCI Insight. 2020;
  22. 22. Vanderwall AG, Milligan ED. Cytokines in Pain: Harnessing Endogenous Anti-Inflammatory Signaling for Improved Pain Management. Frontiers in Immunology. 2019
  23. 23. Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia: Genetic aspects of fibromyalgia syndrome. Arthritis Research and Therapy. 2006
  24. 24. Russell IJ, Larson AA. Neurophysiopathogenesis of Fibromyalgia Syndrome: A Unified Hypothesis. Rheumatic Disease Clinics of North America. 2009
  25. 25. Geenen R, Jacobs JWG, Bijlsma JWJ. Evaluation and management of endocrine dysfunction in fibromyalgia. Rheumatic Disease Clinics of North America. 2002
  26. 26. Bote ME, Garca JJ, Hinchado MD, Ortega E. Inflammatory/stress feedback dysregulation in women with fibromyalgia. Neuroimmunomodulation. 2012;
  27. 27. Bote ME, Garcia JJ, Hinchado MD, Ortega E. Fibromyalgia: Anti-Inflammatory and Stress Responses after Acute Moderate Exercise. PLoS One. 2013;
  28. 28. McLean SA, Williams DA, Stein PK, Harris RE, Lyden AK, Whalen G, et al. Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia. Neuropsychopharmacology. 2006;
  29. 29. Theoharides TC, Stewart JM, Hatziagelaki E. Brain “fog,” inflammation a nd obesity: Key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci. 2015;
  30. 30. Theoharides TC, Petra AI, Stewart JM, Tsilioni I, Panagiotidou S, Akin C. High serum corticotropin-releasing hormone (CRH) and bone marrow mast cell CRH receptor expression in a mastocytosis patient. J Allergy Clin Immunol. 2014;
  31. 31. Giovengo SL, Russell IJ, Larson AA. Increased concentrations of nerve growth factor in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999;
  32. 32. Lewin GR, Lechner SG, Smith ESJ. Nerve growth factor and nociception: From experimental embryology to new analgesic therapy. Handb Exp Pharmacol. 2014;
  33. 33. Lucas HJ, Brauch CM, Settas L, Theoharides TC. Fibromyalgia - New concepts of pathogenesis and treatment. International Journal of Immunopathology and Pharmacology. 2006
  34. 34. Pollack S. Mast cells in fibromyalgia. Clinical and Experimental Rheumatology. 2015
  35. 35. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008
  36. 36. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, et al. Mast cells and inflammation. Biochimica et Biophysica Acta - Molecular Basis of Disease. 2012
  37. 37. Héron A, Dubayle D. A focus on mast cells and pain. Journal of Neuroimmunology. 2013
  38. 38. Chatterjea D, Martinov T. Mast cells: Versatile gatekeepers of pain. Molecular Immunology. 2015
  39. 39. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. New England Journal of Medicine. 2015
  40. 40. Abbadie C. Chemokines, chemokine receptors and pain. Trends in Immunology. 2005
  41. 41. Charo IF, Ransohoff RM. Mechanisms of disease: The many roles of chemokines and chemokine receptors in inflammation. New England Journal of Medicine. 2006
  42. 42. Ross RL, Jones KD, Bennett RM, Ward RL, Druker BJ, Wood LJ. Preliminary Evidence of Increased Pain and Elevated Cytokines in Fibromyalgia Patients with Defective Growth Hormone Response to Exercise. Open Immunol J. 2014;
  43. 43. Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E. Evidence of central inflammation in fibromyalgia - Increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol. 2012;
  44. 44. Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett. 2014;
  45. 45. Meng X, Zhang Y, Lao L, Saito R, Li A, Bäckman CM, et al. Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model. Pain. 2013;
  46. 46. Liu Y, Ho RCM, Mak A. The role of interleukin (IL)-17 in anxiety and depression of patients with rheumatoid arthritis. Int J Rheum Dis. 2012;
  47. 47. Gonçalves dos Santos G, Delay L, Yaksh TL, Corr M. Neuraxial Cytokines in Pain States. Frontiers in Immunology. 2020
  48. 48. von Hehn CA, Baron R, Woolf CJ. Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms. Neuron. 2012
  49. 49. Keller AF, Beggs S, Salter MW, De Koninck Y. Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol Pain. 2007;
  50. 50. Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrøm JB, et al. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain. 2014;
  51. 51. Calvo M, Dawes JM, Bennett DLH. The role of the immune system in the generation of neuropathic pain. The Lancet Neurology. 2012
  52. 52. Beggs S, Trang T, Salter MW. P2X4R + microglia drive neuropathic pain. Nature Neuroscience. 2012
  53. 53. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nature Reviews Immunology. 2014
  54. 54. Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nature Reviews Drug Discovery. 2014
  55. 55. V.A. R, L.P. C, Y. S. Neuroimmunology: What role for autoimmunity, neuroinflammation, and small fiber neuropathy in fibromyalgia, chronic fatigue syndrome, and adverse events after human papillomavirus vaccination? Int J Mol Sci. 2019;
  56. 56. Bäckryd E, Tanum L, Lind AL, Larsson A, Gordh T. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res. 2017;
  57. 57. Dong H, Zhang X, Wang Y, Zhou X, Qian Y, Zhang S. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol Neurobiol. 2017;
  58. 58. Zhang X, Wang Y, Dong H, Xu Y, Zhang S. Induction of microglial activation by mediators released from mast cells. Cell Physiol Biochem. 2016;
  59. 59. Aguzzi A, Barres BA, Bennett ML. Microglia: Scapegoat, saboteur, or something else? Science. 2013
  60. 60. Réu P, Khosravi A, Bernard S, Mold JE, Salehpour M, Alkass K, et al. The Lifespan and Turnover of Microglia in the Human Brain. Cell Rep. 2017;
  61. 61. Groh J, Martini R. Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment. GLIA. 2017
  62. 62. Wang W, Ji P, Riopelle RJ, Dow KE. Functional expression of corticotropin-releasing hormone (CRH) receptor 1 in cultured rat microglia. J Neurochem. 2002;
  63. 63. Thonhoff JR, Simpson EP, Appel SH. Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis. Current opinion in neurology. 2018
  64. 64. Hansson E. Long-term pain, neuroinflammation and glial activation. Scandinavian Journal of Pain. 2010
  65. 65. Blaszczyk L, Maître M, Lesté-Lasserre T, Clark S, Cota D, Oliet SHR, et al. Sequential alteration of microglia and astrocytes in the rat thalamus following spinal nerve ligation. J Neuroinflammation. 2018;
  66. 66. Blottner D, Huang Y, Trautmann G, Sun L. The fascia: Continuum linking bone and myofascial bag for global and local body movement control on Earth and in Space. A scoping review. REACH. 2019
  67. 67. Bordoni B, Lintonbon D, Morabito B. Meaning of the Solid and Liquid Fascia to Reconsider the Model of Biotensegrity. Cureus. 2018;
  68. 68. Hannibal KE, Bishop MD. Chronic stress, cortisol dysfunction, and pain: A psychoneuroendocrine rationale for stress management in pain rehabilitation. Phys Ther. 2014;
  69. 69. Neyal M, Yimenicioglu F, Aydeniz A, Taskin A, Saglam S, Cekmen M, et al. Plasma nitrite levels, total antioxidant status, total oxidant status, and oxidative stress index in patients with tension-type headache and fibromyalgia. Clin Neurol Neurosurg. 2013;
  70. 70. Bozkurt M, Caglayan M, Oktayoglu P, Em S, Batmaz I, Sariyildiz MA, et al. Serum prolidase enzyme activity and oxidative status in patients with fibromyalgia. Redox Rep. 2014;
  71. 71. Ashina M, Bendtsen L, Jensen R, Lassen LH, Sakai F, Olesen J. Possible mechanisms of action of nitric oxide synthase inhibitors in chronic tension-type headache. Brain. 1999;
  72. 72. Ghafourifar P, Cadenas E. Mitochondrial nitric oxide synthase. Trends in Pharmacological Sciences. 2005
  73. 73. Ozgocmen S, Ozyurt H, Sogut S, Akyol O, Ardicoglu O, Yildizhan H. Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: Etiologic and therapeutic concerns. Rheumatol Int. 2006;
  74. 74. Kone BC, Kuncewicz T, Zhang W, Yu ZY. Protein interactions with nitric oxide synthases: Controlling the right time, the right place, and the right amount of nitric oxide. American Journal of Physiology - Renal Physiology. 2003
  75. 75. Sharma JN, Al-Omran A, Parvathy SS. Role of nitric oxide in inflammatory diseases. Inflammopharmacology. 2007
  76. 76. Levy D, Höke A, Zochodne DW. Local expression of inducible nitric oxide synthase in an animal model of neuropathic pain. Neurosci Lett. 1999;
  77. 77. Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y. Prostaglandin E2-induced inflammation: Relevance of prostaglandin e receptors. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2015
  78. 78. Santa-Cecília F V., Ferreira DW, Guimaraes RM, Cecilio NT, Fonseca MM, Lopes AH, et al. The NOD2 signaling in peripheral macrophages contributes to neuropathic pain development. Pain. 2019;
  79. 79. Thacker MA, Clark AK, Marchand F, McMahon SB. Pathophysiology of peripheral neuropathic pain: Immune cells and molecules. Anesthesia and Analgesia. 2007
  80. 80. Kiguchi N, Kobayashi Y, Kishioka S. Chemokines and cytokines in neuroinflammation leading to neuropathic pain. Current Opinion in Pharmacology. 2012
  81. 81. Ristoiu V. Contribution of macrophages to peripheral neuropathic pain pathogenesis. Life Sciences. 2013
  82. 82. Okifuji A, Gao J, Bokat C, Hare BD. Management of fibromyalgia syndrome in 2016. Pain management. 2016
  83. 83. Häuser W, Bernardy K, Arnold B, Offenbächer M, Schiltenwolf M. Efficacy of multicomponent treatment in fibromyalgia syndrome: A meta-analysis of randomized controlled clinical trials. Arthritis Care Res. 2009;
  84. 84. Üçeyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C. Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum. 2006;
  85. 85. Sturgill J, McGee E, Menzies V. Unique cytokine signature in the plasma of patients with fibromyalgia. J Immunol Res. 2014;
  86. 86. Clauw DJ. Fibromyalgia: A clinical review. JAMA - Journal of the American Medical Association. 2014
  87. 87. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. Journal of the American Medical Association. 2004
  88. 88. Fitzcharles MA, Ste-Marie PA, Goldenberg DL, Pereira JX, Abbey S, Choinière M, et al. Canadian pain society and canadian rheumatology association recommendations for rational care of persons with fibromyalgia. A summary report. J Rheumatol. 2013;
  89. 89. Busch AJ, Webber SC, Richards RS, Bidonde J, Schachter CL, Schafer LA, et al. Resistance exercise training for fibromyalgia. Cochrane Database of Systematic Reviews. 2013
  90. 90. Bidonde J, Busch AJ, Webber SC, Schachter CL, Danyliw A, Overend TJ, et al. Aquatic exercise training for fibromyalgia. Cochrane Database of Systematic Reviews. 2014
  91. 91. Mist SD, Firestone KA, Jones KD. Complementary and alternative exercise for fibromyalgia: A meta-analysis. Journal of Pain Research. 2013
  92. 92. Sawynok J, Lynch M. Qigong and fibromyalgia: Randomized controlled trials and beyond. Evidence-based Complementary and Alternative Medicine. 2014
  93. 93. Porter NS, Jason LA, Boulton A, Bothne N, Coleman B. Alternative medical interventions used in the treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia. J Altern Complement Med. 2010;
  94. 94. Arranz LI, Canela MÁ, Rafecas M. Dietary aspects in fibromyalgia patients: Results of a survey on food awareness, allergies, and nutritional supplementation. Rheumatol Int. 2012;
  95. 95. Cordero MD, Cano-García FJ, Alcocer-Gómez E, de Miguel M, Sánchez-Alcázar JA. Oxidative stress correlates with headache symptoms in Fibromyalgia: Coenzyme Q 10 effect on clinical improvement. PLoS One. 2012;
  96. 96. Cordero MD, Cotán D, del-Pozo-Martín Y, Carrión AM, de Miguel M, Bullón P, et al. Oral coenzyme Q10 supplementation improves clinical symptoms and recovers pathologic alterations in blood mononuclear cells in a fibromyalgia patient. Nutrition. 2012;
  97. 97. Rossini M, Di Munno O, Valentini G, Bianchi G, Biasi G, Cacace E, et al. Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients. Clin Exp Rheumatol. 2007;
  98. 98. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacological Reviews. 2000
  99. 99. Cazarolli L, Zanatta L, Alberton E, Bonorino Figueiredo MS, Folador P, Damazio R, et al. Flavonoids: Prospective Drug Candidates. Mini-Reviews Med Chem. 2008;
  100. 100. Izzi V, Masuelli L, Tresoldi I, Sacchetti P, Modesti A, Galvano F, et al. The effects of dietary flavonoids on the regulation of redox inflammatory networks. Frontiers in Bioscience. 2012
  101. 101. Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Effects of luteolin, quercetin and baicalein on immunoglobulin E- mediated mediator release from human cultured mast cells. Clin Exp Allergy. 2000;
  102. 102. Jäger AK, Saaby L. Flavonoids and the CNS. Molecules. 2011
  103. 103. Grosso C, Valentão P, Ferreres F, Andrade P. The Use of Flavonoids in Central Nervous System Disorders. Curr Med Chem. 2013;
  104. 104. Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Flub E, et al. EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis. 2017;
  105. 105. Häuser W, Arnold B, Eich W, Felde E, Flügge C, Henningsen P, et al. Management of fibromyalgia syndrome--an interdisciplinary evidence-based guideline. Ger Med Sci. 2008;
  106. 106. Häuser W, Petzke F, Üeyler N, Sommer C. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: A systematic review with meta-analysis. Rheumatology. 2011;
  107. 107. Clemons A, Vasiadi M, Kempuraj D, Kourelis T, Vandoros G, Theoharides TC. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: Possible relevance to chronic fatigue syndrome. Journal of Clinical Psychopharmacology. 2011
  108. 108. Harris RE, Napadow V, Huggins JP, Pauer L, Kim J, Hampson J, et al. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology. 2013;
  109. 109. Häuser W, Bernardy K, Üçeyler N, Sommer C. Treatment of fibromyalgia syndrome with gabapentin and pregabalin - A meta-analysis of randomized controlled trials. Pain. 2009;
  110. 110. Häuser W, Bernardy K, Üçeyler N, Sommer C. Treatment of fibromyalgia syndrome with antidepressants: A meta-analysis. JAMA - Journal of the American Medical Association. 2009
  111. 111. Moore RA, Wiffen PJ, Derry S, Rice ASC. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2014
  112. 112. Derry S, Wiffen PJ, Häuser W, Mücke M, Tölle TR, Bell RF, et al. Oral nonsteroidal anti-inflammatory drugs for fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2017
  113. 113. Moldofsky H, Harris HW,Tad Archambault W, Kwong T, Lederman S. Effects of bedtime very low dose cyclobenzaprine on symptoms and sleep physiology in patients with fibromyalgia syndrome: A double-blind randomized placebo-controlled study. J Rheumatol. 2011;
  114. 114. Lunn MPT, Hughes RAC, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews. 2014
  115. 115. Arnold LM, Rosen A, Pritchett YL, D’Souza DN, Goldstein DJ, Iyengar S, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;
  116. 116. Russell IJ. Fibromyalgia syndrome: Approach to management. CNS Spectrums. 2008
  117. 117. Calandre EP, Rico-Villademoros F, Slim M. An update on pharmacotherapy for the treatment of fibromyalgia. Expert Opinion on Pharmacotherapy. 2015
  118. 118. Welsch P, Üçeyler N, Klose P, Walitt B, Häuser W. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database of Systematic Reviews. 2018
  119. 119. Krell H V., Leuchter AF, Cook IA, Abrams M. Evaluation of reboxetine, a noradrenergic antidepressant, for the treatment of fibromyalgia and chronic low back pain. Psychosomatics. 2005
  120. 120. Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B. Safety and efficacy of esreboxetine in patients with fibromyalgia: A fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2012;
  121. 121. Ablin J, Fitzcharles MA, Buskila D, Shir Y, Sommer C, Häuser W. Treatment of fibromyalgia syndrome: Recommendations of recent evidence-based interdisciplinary guidelines with special emphasis on complementary and alternative therapies. Evidence-based Complementary and Alternative Medicine. 2013
  122. 122. Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, et al. Pregabalin for the treatment of Fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;
  123. 123. Ohta H, Oka H, Usui C, Ohkura M, Suzuki M, Nishioka K. A randomized, double-blind, multicenter, placebo-controlled phase III trial to evaluate the efficacy and safety of pregabalin in Japanese patients with fibromyalgia. Arthritis Res Ther. 2012;
  124. 124. Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;
  125. 125. Skrabek RQ , Galimova L, Ethans K, Perry D. Nabilone for the Treatment of Pain in Fibromyalgia. J Pain. 2008;
  126. 126. Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: Results of a randomized controlled trial. Anesth Analg. 2010;
  127. 127. Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W. Cannabinoids for fibromyalgia. Cochrane Database of Systematic Reviews. 2016
  128. 128. Konrad C, Weber J, Schley M, Casutt M, Gerber H, Schuepfer G, et al. Tetrahydrocannabinol (Delta 9-THC) treatment in chronic central neuropathic pain and fibromyalgia patients: Results of a multicenter survey. Anesthesiology Research and Practice. 2009
  129. 129. Cohen SP, Verdolin MH, Chang AS, Kurihara C, Morlando BJ, Mao J. The Intravenous Ketamine Test Predicts Subsequent Response to an Oral Dextromethorphan Treatment Regimen in Fibromyalgia Patients. J Pain. 2006;
  130. 130. Johnson JW, Kotermanski SE. Mechanism of action of memantine. Current Opinion in Pharmacology. 2006
  131. 131. Harris RE, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, et al. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 2009;
  132. 132. Olivan-Blázquez B, Herrera-Mercadal P, Puebla-Guedea M, Pérez-Yus MC, Andrés E, Fayed N, et al. Efficacy of memantine in the treatment of fibromyalgia: A double-blind, randomised, controlled trial with 6-month follow-up. Pain. 2014;
  133. 133. Akinkunle Fadare SO. Relief and Resolution of Fibromyalgia Symptoms with Low Dose Methotrexate – The Origin of Pain is Inflammation and the Inflammatory Response. Rheumatol Curr Res. 2014;
  134. 134. Chakr RM da S, Brenol C, Ranzolin A, Bernardes A, Dalosto AP, Ferrari G, et al. Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia. Rev Bras Reumatol (English Ed. 2017;
  135. 135. Salaffi F, Gerardi MC, Atzeni F, Batticciotto A, Talotta R, Draghessi A, et al. The influence of fibromyalgia on achieving remission in patients with long-standing rheumatoid arthritis. Rheumatol Int. 2017;
  136. 136. Wang H, Buchner M, Moser MT, Daniel V, Schiltenwolf M. The role of IL-8 in patients with fibromyalgia: A prospective longitudinal study of 6 months. Clin J Pain. 2009;
  137. 137. Cordero MD, Alcocer-Gómez E, Culic O, Carrión AM, De Miguel M, Díaz-Parrado E, et al. NLRP3 inflammasome is activated in fibromyalgia: The effect of coenzyme Q10. Antioxidants and Redox Signaling. 2014
  138. 138. Tsai RY, Jang FL, Tai YH, Lin SL, Shen CH, Wong CS. Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats. Neuropsychopharmacology. 2008;
  139. 139. Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, et al. Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther. 2000;
  140. 140. Greeneltch KM, Haudenschild CC, Keegan AD, Shi Y. The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-α production. Brain Behav Immun. 2004;
  141. 141. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: A pilot study. Pain Med. 2009;
  142. 142. Wang H, Yu M, Ochani M, Amelia CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 2003;
  143. 143. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol. 2005;
  144. 144. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. Journal of Clinical Investigation. 2007
  145. 145. Borovikova L V., Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;
  146. 146. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nature Reviews Drug Discovery. 2005
  147. 147. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;
  148. 148. Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med. 2005;

Written By

Vishwas Tripathi, Amaresh Mishra, Yamini Pathak, Aklank Jain and Hridayesh Prakash

Submitted: 14 August 2020 Reviewed: 14 October 2020 Published: 30 October 2020