Neurological Aspects and Phenomena in Fibromyalgia

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Partial list of aspects[edit]

[This list was largely summarized from (Neurobiology Underlying Fibromyalgia Symptoms. Marta Ceko, M. Catherine Bushnell, and Richard H. Gracely, Pain Research and Treatment, 2012, 585419 available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205654/.)]

  • chronic widespread pain
  • altered pain modulatory mechanisms,
  • increased sensitivity to painful stimuli,
  • increased sensitivity to multiple sensory modalities,
  • altered inhibition
  • cognitive change aspects
  • sleep aspects including altered levels of neurotransmitters involved in sleep regulation
  • other aspects of central sensitization

[Author’s comments: The existence of these aspects can be viewed as part of the overall case that fibromyalgia is first and foremost a disorder of the nervous system, and especially the central nervous system with its many subsystems for pain, sleep and cognition.]

Altered frontal and cerebellar structural covariance brain networks[edit]

Kim et al. found that fibromyalgia is characterized by altered frontal and cerebellar structural covariance brain networks. (Fibromyalgia is characterized by altered frontal and cerebellar structural covariance brain networks. Kim H, Kim J, Loggia ML, Cahalan C, Garcia RG, Vangel MG, et al. Neuroimage Clin. 2015;7:667–77. [PMC free article] [PubMed] [Google Scholar]) For a diagram that helps clarify this see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379388/figure/f0015/.

The author’s summarized their findings by saying that they conducted structural covariance network analysis. This demonstrated denser connections in FM patients in the cerebellum. Healthy controls had denser frontal lobe connections. Spectral partitioning helped find that there were dense cerebellar connections to the medial prefrontal/orbitofrontal cortex, medial temporal lobe, and right inferior parietal lobule in FM patients.

Altered reward-punishment circuits[edit]

Logia et al. conducted a study of “potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain” such as pain anticipation and the anticipation of pain relief. Cuff pressure was applied to the leg used to stimulate pain to a level of approximately 50 out of 100, and fMRI was conducted. While being scanned “received visual cues informing them of the impending onset of pain (pain anticipation) and the impending offset of pain (relief anticipation).” Results showed that the fibromyalgia patients had less robust activations the anticipation of pain and anticipation of relief in the regions of the brain commonly believed to be involved in sensory, affective, cognitive, and pain-modulatory processes. In health controls, the ventral tegmental area demonstrated a “pattern of activity compatible with the encoding of punishment signals: activation during anticipation of pain and pain stimulation, but deactivation during anticipation of pain relief.”

In FM patients, ventral tegmental area activity during periods of pain and periods of anticipation of pain and anticipation of pain relief was great reduced or absent.

The authors concluded that in fibromyalgia there is a disruption of the brain responses to reward/punishment. They note that it is known that the “ventral tegmental area is a source of reward-linked dopaminergic/γ-aminobutyric acid-releasing (GABAergic) neurotransmission in the brain…” They argue that their “observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM.” They explain that there is a reduction in reward/punishment signaling in FM and that this “may be related to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients.” (Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Loggia ML, Berna C, Kim J, Cahalan CM, Gollub RL, Wasan AD, et al. Arthritis Rheumatol. 2014;66(1):203–12. [PMC free article] [PubMed] [Google Scholar] available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516215/.

Possible role of the anterior cingulate in allodynia and over-reactions to pressing on tender points in patients with fibromyalgia[edit]

The anterior cingulate has a sub-region for processing noxious stimuli. Clinical experience shows that in moderate of severe cases of fibromyalgia, when the patient is pressed on one of their tender points, they also complain of pain they sometimes vocalize their pain by moaning or groaning. The anterior cingulate is known to have a pain vocalization area and so the quest arises as to whether it is being activated in this situation. Clinical experience indicates that these same patients tend also to have involuntary nociceptive pain withdrawal reflexes. (It is conceivable that this involves connections between the anterior cingulate and the red nucleus and the spinal cord).

It is known that the anterior cingulate is involved in “assigning emotional valence to internal and external stimuli” (Devinsky, 1995). Perhaps this applies to the tender points and accounts for aspects of the over-reactions to tender point pressure whereby clinical experience shows that some patients exhibit evidence of emotional objection to pressure applied to them during the physical exam. This is apparent as facial grimaces and wincing around the eyes and in some cases by a tone of protest in their voice when the tender points are pressed above their pressure pain threshold.

Perhaps one day treatments could be designed in which the emotional valance assigned to stimuli such as this were more positive, then perhaps the over-reactions just described such as withdrawal reflexes and vocalizations would subside.

Role of PAG connectivity[edit]

A study by Truini et al. began by noting the mounting evidence in the literature that various chronic pain syndromes including fibromyalgia involves “endogenous pain modulatory system dysfunction, leading to an impaired descending pain inhibition”.

They used resting-state functional magnetic resonance imaging (fMRI) in fibromyalgia to look for functional connectivity changes of the periaqueductal gray (PAG) which is known to be part of the pain modulatory system.

They looked for correlations “between clinical variables, such as pain severity, disease duration, and depressive personality traits with PAG functional connectivity.” In the resting state they found “an increased PAG connectivity with insula, anteriorcingulate cortex, and anterior prefrontal cortex. The functional connectivity between PAG and the rostral ventral medulla, however, was not concordantly increased. PAG functional connectivity correlated with pain severity, disease duration, and the depressive personality trait rating.” They concluded that their findings suggest “that patients with fibromyalgia have an endogenous pain modulatory system dysfunction, possibly causing an impaired descending pain inhibition.” (Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia.” Truini A1, Tinelli E1, Gerardi MC2, Calistri V3, Iannuccelli C4, La Cesa S1, Tarsitani L1, Mainero C5, Sarzi-Puttini P6, Cruccu G1, Caramia F1, Di Franco M4. Clin Exp Rheumatol. 2016 May-Jun;34(2 Suppl 96):129-33.)

Imbalance in facilitation in pain processing[edit]

Sensory amplification “enhanced receptive field characteristics of the disease may be explained as a consequence of increased neuronal membrane excitability, synaptic facilitation and nociceptive pathway disinhibition mediated at the molecular level by the modification of receptor kinetics (e.g., N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)) and at the cellular level by the interaction of both neurons and microglia interchanging neurotransmitters and inflammatory cytokines (e.g., substance P, tumor necrosis factor alpha, and brain-derived neurotrophic factor (BDNF)), which results in enhanced neuronal and nociceptive pathway functions [8-10].” (Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Zanette SA, Dussan-Sarria JA, Souza A, Deitos A, Torres IL, Caumo W. Mol Pain. 2014 Jul 8;10:46 available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094546/.)

Central sensitization[edit]

Numerous studies have provided evidence for central sensitization in fibromyalgia. (For an article that lists a number of them see: Central sensitization: Implications for the diagnosis and treatment of pain, Clifford J Woolf, Pain. 2011 Mar; 152(3 Suppl): S2–15, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268359/)

Neural Basis of Pain Amplification and Altered Pain Modulation[edit]

Ceko et al. write: “Functional brain imaging studies support psychophysical findings of increased pain perception in FM, in that there is an augmentation of sensory processing throughout pain-related brain regions [9, 76–81]. This is important, since laboratory findings of increased sensitivity could be interpreted as a reporting bias, rather than evidence of increased activation in pain pathways. The functional imaging studies have found that fibromyalgia patients show significantly more activity in response to pressure and thermal stimuli compared to controls in a number of brain regions. Increased activations were observed not only in limbic structures, but also in brain regions involved in sensory-discriminative processing, such as primary and secondary somatosensory cortices, which supports the view that neural responses to afferent signals are amplified in fibromyalgia.

Although the increased pain-evoked brain activations corroborate patients' reports, the correlation between increased brain activity and increased pain perception does not explain how the afferent signal is amplified. As discussed above, there is psychophysical evidence of dysfunctions in pain modulation as well as pain perception. There is now much evidence that the activation of descending control circuitry is involved in pain modulation and that this circuitry includes parts of prefrontal, cingulate, and insular cortices [23, 36, 37, 82, 83]. A number of anatomical imaging studies in FM patients reveal decreased brain gray matter in these regions [84–90]. Although the cellular basis of decreased gray matter in FM patients is not known, it is possible that due to neuronal loss, decreased dendritic arborisation, or changes in glial activation, pain inhibitory systems do not work in FM patients as well as in healthy individuals.

Consistent with the idea that pain modulatory systems may be disturbed in fibromyalgia are data showing that some FM patients have abnormalities in neurochemical systems involved in pain control, including the forebrain opioid and dopamine systems. A positron emission tomography (PET) competitive binding study using the D2/D3 receptor antagonist [11C] raclopride showed that striatal dopamine is released in response to painful muscle stimulation in healthy subjects, but not in FM patients [15, 91], which might partially explain the increased sensitivity of FM patients to the painful muscle stimulation.”

Resting EEG changes[edit]

A study with resting EEG of fibromyalgia patients examined the patients using the Manual Tender Point Scale in order to “quantify tonic pain and tenderness on the day of testing” while also taking measure of mood, arousal and fatigue. (Altered theta oscillations in resting EEG of fibromyalgia syndrome patients, N. Fallon , Y. Chiu . T. Nurmikko, A. Stancak. European Journal of Pain, 31 July 2017, https://doi.org/10.1002/ejp.1076, available in full online at: https://onlinelibrary.wiley.com/doi/full/10.1002/ejp.1076.) As expected, fibromyalgia patients had greater pain, tiredness and tension on the test day compared to health controls. They also had augmented theta activity in prefrontal and anterior cingulate cortices. This augmented theta correlated with measures of tenderness and mean tiredness scores.

Changes in the primary somatosensory cortex (S1), supplementary motor area (SMA), dorsolateral prefrontal cortex, and amygdala[edit]

A study by Kim et al found that patients with FM exhibited significantly increased frequency power in the primary somatosensory cortex (S1), supplementary motor area (SMA), dorsolateral prefrontal cortex, and amygdala. They found atypical increased frequency power during the resting state in pain-related brain regions may implicate the enhanced resting-state baseline neural activity in several brain regions associated with pain processing in FM. (Increased power spectral density in resting-state pain-related brain networks in fibromyalgia. Kim JY1, Kim SH, Seo J, Kim SH, Han SW, Nam EJ, Kim SK, Lee HJ, Lee SJ, Kim YT, Chang Y. Pain. 2013 Sep;154(9):1792-7.)

Resting state functional connectivity changes involving the insula[edit]

Fibromyalgia is “associated with heightened responses to painful stimuli and atypical resting-state functional connectivity among pain-related regions of the brain.” (Increased power spectral density in resting-state pain-related brain networks in fibromyalgia. Kim JY1, Kim SH, Seo J, Kim SH, Han SW, Nam EJ, Kim SK, Lee HJ, Lee SJ, Kim YT, Chang Y. Pain. 2013 Sep;154(9):1792-7. ) A study by Ichesco et al. noted that the insular cortex (IC) and cingulate cortex (CC) are known to be of critical importance in pain perception. (Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. Ichesco E1, Schmidt-Wilcke T2, Bhavsar R3, Clauw DJ4, Peltier SJ5, Kim J6, Napadow V7, Hampson JP4, Kairys AE8, Williams DA4, Harris RE4 J Pain, 2014 Aug;15(8):815-826.e1..available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127388/.)

One of their studies found that fibromyalgia patients have high “connectivity between the insula and default mode network at rest…” They also found that “changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain.”

In a later study of the resting state they assessed functional connectivity with magnetic resonance imaging. They made use of predefined seed regions in the anterior, middle, and posterior IC.

Results showed that fibromyalgia patients had greater connectivity between the following areas:

1) the right mid IC and right mid/posterior CC and right mid IC,

2) right posterior IC and left CC, and

3) right anterior IC and left superior temporal gyrus.

Healthy controls had more “connectivity between left anterior IC and bilateral medial frontal gyrus/anterior cingulate cortex; and left posterior IC and right superior frontal gyrus.”

For the fibromyalgia patients the “greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds.”

Chemical changes in the VLPFC[edit]

A study by Feraco et al. found that fibromyalgia patients have high Glx/Cr and Glu/Cr ratios within their ventrolateral prefrontal cortex (VLPFC) on both sides. (Metabolic Abnormalities in Pain-Processing Regions of Patients with Fibromyalgia: A 3T MR Spectroscopy Study. P. Feraco, A. Bacci, Fab. Pedrabissi, L. Passamonti, G. Zampogna, Fed. Pedrabissi, N. Malavolta and M. Leonardi, American Journal of Neuroradiology, October 2011, 32 (9) 1585-1590; DOI: https://doi.org/10.3174/ajnr.A2550, available in full online at: http://www.ajnr.org/content/ajnr/32/9/1585.full.pdf.)

Retrosplenial cortical deactivation (during painful stimulation of fibromyalgia patients)[edit]

This phenomenon has been found in a small study of fibromyalgia patients using PET scans during induced acute pain. Results showed reduced activation in the retrosplenial cortex during acute pain as compared to rest. The authors hypothesized that the reason might be related to what they called “evaluative processes located in the retrosplenial cortex”. (For further information see: Retrosplenial cortical deactivation during painful stimulation of fibromyalgic patients, Wik G, Fischer H, Finer B, Bragee B, Kristianson M, Fredrikson M. Int J Neurosci. 2006 Jan;116(1):1-8.) The retrosplenial cortex is comprised of Brodmann areas 29 and 30.

Neuro-biochemical changes in fibromyalgia[edit]

Transmitter systems.png
Alterations in transmitter systems found in fibromyalgia patients in terms of increased or decreased activity and action of drugs used in fibromyalgia on these transmitters systems in terms of activity increase or decrease.
This is figure 1 from: Dysfunctional Neurotransmitter Systems in Fibromyalgia, Their Role in Central Stress Circuitry and Pharmacological Actions on These Systems. https://www.hindawi.com/journals/prt/2012/741746/fig1/ Susanne Becker and Petra Schweinhardt, Pain Research and Treatment, Volume 2012 (2012), Article ID 741746, available in full online at: http://dx.doi.org/10.1155/2012/741746 and made available under a Creative Commons attribution 3.0 Unported license (CC BY 3.0) which includes commercial use. For further details see: https://www.hindawi.com/journals/prt/2012/741746/tab1/.


Substance P[edit]

Russell stated that in fibromyalgia: “The most dramatic and consistent finding to date has been elevated levels of substance P [SP] in fibromyalgia syndrome cerebrospinal fluid [CSF]. Statistical correlations of pain measures with CSF SP or time delta CSF SP in fibromyalgia syndrome both support the hypothesis that CSF SP may be pathogenic. The production of CSF SP can be enhanced by ongoing peripheral pain, elevated CSF nerve growth factor, or CSF dynorphin A, all documented in fibromyalgia syndrome.” (Neurochemical Pathogenesis of Fibromyalgia Syndrome, Irwin Jon Russell, Journal of Musculoskeletal Pain 7(1-2):183-191, January 2010.) 

For an image suggesting that substance P is part of the ascending pathway/ facilitation in fibromyalgia and also showing neurochemicals involved in the descending pathways/inhibition see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258006/figure/F3/.

Opioidergic activity in fibromyalgia[edit]

Harris et al state: “In fibromyalgia, the accumulating data suggests that opioid-ergic activity is normal or even increased, in that concentrations of cerebrospinal fluid (CSF) enkephalins are roughly twice as high in fibromyalgia and idiopathic low back pain patients as compared to healthy controls.15 Moreover, PET data show that baseline mu-opioid receptor binding is decreased in multiple pain processing regions in the brains of fibromyalgia patients, consistent (but not pathognomonic) with the hypothesis that there is increased release of endogenous mu-opioid ligands in fibromyalgia leading to high baseline occupancy of the receptors.” (Newer treatments for fibromyalgia syndrome. Richard E Harris and Daniel J Clauw, Ther Clin Risk Manag. 2008 Dec; 4(6): 1331–1342.)

“The biochemical and imaging findings suggesting altered activity of endogenous opioidergic systems in fibromyalgia are consistent with the anecdotal experience that opioids are generally ineffective analgesics in patients with fibromyalgia and related conditions.” (Newer treatments for fibromyalgia syndrome. Richard E Harris and Daniel J Clauw, Ther Clin Risk Manag. 2008 Dec; 4(6): 1331–1342.)

Serotonergic and noradrenergic activity in fibromyalgia[edit]

Harris et al. state that studies show the relevance of serotonergic and noradrenergic activity in fibromyalgia and that “principal metabolite of norepinephrine, 3-methoxy-4-hydroxyphenethylene (MPHG), is lower in the CSF of fibromyalgia patients (Russell et al 1992). Similarly, there are data suggesting low serotonin in this syndrome. Patients with fibromyalgia were shown to have reduced serum levels of serotonin and its precursor, L-tryptophan, as well as reduced levels of the principal serotonin metabolite, 5-HIAA, in their CSF (Russell et al 1992; Yunus et al 1992). Further evidence for this mechanism comes from treatment studies, where nearly any type of compound that simultaneously raises both serotonin and norepinephrine has been shown to be efficacious in treating fibromyalgia and related conditions (Arnold et al 2000, 2004b; Bennett et al 2003; Gendreau et al 2005).” (Newer treatments for fibromyalgia syndrome. Richard E Harris and Daniel J Clauw, Ther Clin Risk Manag. 2008 Dec; 4(6): 1331–1342.)

Neurochemical aspects of antinociception[edit]

Russell stated that in fibromyalgia: “Failure of antinociception could result from low metenkephalin or low serotonin, both observed in fibromyalgia syndrome… Cerebrospinal fluid SP correlates with decreased brain regional blood flow. Many other bodily functions are influenced by these same mediators. Conclusions: The widespread body pain and tenderness which characterize fibromyalgia syndrome could result from central pain amplification by mediators of nociception. Abnormalities in fibromyalgia syndrome brain regional blood flow, neuroendocrine function, autonomic neural function, and intestinal motility could also relate to central neurotransmitter imbalance.” (Neurochemical Pathogenesis of Fibromyalgia Syndrome, Irwin Jon Russell, Journal of Musculoskeletal Pain 7(1-2):183-191, January 2010.) 

Serum brain-derived neurotrophic factor in[edit]

High serum brain-derived neurotrophic factor (BDNF) occurs in fibromyalgia. “BDNF is a neurotrophic factor that is widely distributed in the central nervous system (CNS) and is capable of strengthening excitatory (glutamatergic) synapses as well as weakening inhibitory (GABAergic) synapses.” (Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Zanette SA, Dussan-Sarria JA, Souza A, Deitos A, Torres IL, Caumo W. Mol Pain. 2014 Jul 8;10:46, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094546/.)

Zanette et al. studied the association between fibromyalgia and BDNF and S100B (a protein which “regulates neuroglia [sic] functions and which is a traditional “proxy of central nervous system damage”). They said that both chemicals are “key mediators in the central sensitization process” and are “inversely correlated” with the pressure pain thresholds. The concluded that: “Serum assessment of BDNF and S100B deserve further study to determine its potential as a proxy for the central sensitization spectrum in fibromyalgia.” (Zanette et al. 2014)

[Author’s comment: This is one of a great number of biochemical abnormalities that have been found in fibromyalgia. Because the disease is so complex and multilayer, great caution is needed to as not to jump to the conclusion that a drug aimed at any one of these abnormalities can or will effect an overall clinically significant change in patients.]

Zanette et al. 2014 also note that: “Although circulating levels of BDNF have been found to be elevated in FM [fibromyalgia] compared with controls, its association with the patients’ clinical complaints remains elusive.” They further state: “Despite known role of astrocytes and microglia in the CS [16], surrogates of their activity other than BDNF have been scarcely explored in FM patients. S100B is a Ca2+-binding protein that, at higher concentrations, upregulates Interleukin-1β and Tumor Necrosis Factor α expression and activates the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) via the receptor for advanced glycation end products (RAGE) in microglia and astrocytes [17,18], all of which are involved in CS [central sensitization]progression and maintenance [8]. Elevated S100B serum levels have been correlated with mood disorders [19] and have been studied as an outcome predictor in severe traumatic brain injury [20, 21] but have not been previously explored in a chronic pain syndrome.” (Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia. Zanette SA, Dussan-Sarria JA, Souza A, Deitos A, Torres IL, Caumo W. Mol Pain. 2014 Jul 8;10:46 available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094546/.)

For additional articles about BDNF in fibromyalgia see[edit]

A brain-derived neurotrophic factor polymorphism Val66Met identifies fibromy-algia syndrome subgroup with higher body mass index and C-reactive protein. Xiao Y, Russell IJ, Liu YG. Rheumatol Int. 2012 Aug;32(8):2479-85.

Increased plasma levels of brain derived neurotrophic factor (BDNF) in patients with fibromyalgia. Haas L, Portela LV, Böhmer AE, Oses JP, Lara DR. Neurochem Res. 2010 May;35(5):830-4.

Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. Sarchielli P, Mancini ML, Floridi A, Coppola F, Rossi C, Nardi K, Acciarresi M, Pini LA, Calabresi P. J Pain. 2007 Sep;8(9):737-45.

Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. Laske C, Stransky E, Eschweiler GW, Klein R, Wittorf A, Leyhe T, Richartz E, Köhler N, Bartels M, Buchkremer G, Schott K. J Psychiatr Res. 2007 Oct;41(7):600-5.

Serum level of brain-derived neurotrophic factor in fibromyalgia syndrome cor-relates with depression but not anxiety. Nugraha B, Korallus C, Gutenbrunner C. Neurochem Int. 2013 Feb;62(3):281-6.

Brain-derived neurotrophic factor and exercise in fibromyalgia syndrome patients: a mini review. Nugraha B, Karst M, Engeli S, Gutenbrunner C. Rheumatol Int. 2012 Sep;32(9):2593-9.

Glutamate[edit]

Clauw et al. wrote: “Neurotransmitters that generally act to increase ascending input, including substance P, nerve growth factor, and brain-derived neurotrophic factor, are present in higher levels in the CSF of patients with fibromyalgia than healthy controls. Additionally, levels of glutamate and other excitatory amino acids have been shown to be elevated in both the CSF and brain in individuals with fibromyalgia. Glutamate acts on N-methyl-d-aspartate receptors to produce increased pain “wind up,” a phenomenon of progressively increased central pain amplification after repeated painful stimulation, resulting in greater hyperalgesia and allodynia.” (The Science of Fibromyalgia. Daniel J. Clauw, MD, Lesley M. Arnold, MD, and Bill H. McCarberg, MD, Mayo Clin Proc. 2011 Sep; 86(9): 907–91, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258006/.)

Furthermore, glutamate is elevated in the insula in fibromyalgia. (Elevated insular glutamate in fibromyalgia is associated with experimental pain. Harris RE1, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, Clauw DJ. Arthritis Rheum. 2009 Oct;60(10):3146-52.)

For a diagram entitled “Neural pathways and neurotransmitters that influence pain sensitivity” see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258006/figure/F3/. (It was adapted from Rheum Dis Clin N Am,13 with permission from Elsevier.) It lists the following neurochemicals as participating in the “ascending pathway/facilitation”: substance P, nerve growth factor and glutamate.

It also lists the following neurochemicals as participating in the “descending path-way/ inhibition: norepinephrine, serotonin and dopamine. For details see the original articles.