The DOI matches its Crossref record; 231 of the 235 references it cites were found in a registry or an index, and 1 are not checked yet.
Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions
Open accessAbstract
Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, migraine, and temporomandibular disorder. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life. The high degree of symptom comorbidity and a lack of definitive underlying etiology make these syndromes notoriously difficult to treat. The main purpose of this review article is to discuss potential mechanisms of centrally-driven pain amplification and how they may contribute to increased comorbidity, poorer pain outcomes, and decreased quality of life in patients diagnosed with centralized pain syndromes, as well as discuss emerging non-pharmacological therapies that improve symptomology associated with these syndromes. Abnormal regulation and output of the hypothalamic-pituitary-adrenal (HPA) axis is commonly associated with centralized pain disorders. The HPA axis is the primary stress response system and its activation results in downstream production of cortisol and a dampening of the immune response. Patients with centralized pain syndromes often present with hyper- or hypocortisolism and evidence of altered downstream signaling from the HPA axis including increased Mast cell (MC) infiltration and activation, which can lead to sensitization of nearby nociceptive afferents. Increased peripheral input via nociceptor activation can lead to "hyperalgesic priming" and/or "wind-up" and eventually to central sensitization through long term potentiation in the central nervous system. Other evidence of central modifications has been observed through brain imaging studies of functional connectivity and magnetic resonance spectroscopy and are shown to contribute to the widespreadness of pain and poor mood in patients with fibromyalgia and chronic urological pain. Non-pharmacological therapeutics, including exercise and cognitive behavioral therapy (CBT), have shown great promise in treating symptoms of centralized pain.
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“Local infiltration and migration of mast cells, leading to sensitization of nearby nociceptive afferents, are considered vital contributors to NPP pathogenesis (69).”
From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [69]
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“NPP is widely reported to be correlated with mast cell activation.”
From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [69]
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Items 201–232 of 232
Harper, D., Ichesco, E., Schrepf, A., Halvorson, M., Puiu, T., Clauw, D. J., Harris, R. E., & Harte, S. E. (2017) · NeuroImage Clinical · doi:10.1016/j.nicl.2017.11.014 · Cited by 55
The relationship between sexual abuse and interstitial cystitis/painful bladder syndrome
Mayson, B. E., & Teichman, J. M. H. (2009) · Current Urology Reports · doi:10.1007/s11934-009-0070-3 · Cited by 54
Merrill, L., Malley, S. E., & Vizzard, M. A. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00089.2013 · Cited by 54
Quantifying mast cells in bladder pain syndrome by immunohistochemical analysis
Larsen, M. S., Mortensen, S., Nordling, J., & Horn, T. D. (2008) · British Journal of Urology · doi:10.1111/j.1464-410x.2008.07576.x · Cited by 54
Zhang, X.-C., & Levy, D. (2008) · Cephalalgia · doi:10.1111/j.1468-2982.2007.01523.x · Cited by 53
Interstitial Cystitis/Bladder Pain Syndrome and Nonbladder Syndromes: Facts and Hypotheses
Warren, J. W., van de Merwe, J. P., & Nickel, J. C. (2011) · Urology · doi:10.1016/j.urology.2011.06.014 · Cited by 52
Coste, J., Voisin, D. L., Luccarini, P., & Dallel, R. (2008) · Cephalalgia · doi:10.1111/j.1468-2982.2008.01568.x · Cited by 51
van den Wijngaard, R. M., Stanisor, O. I., van Diest, S. A., Welting, O., Wouters, M. M., de Jonge, W. J., & Boeckxstaens, G. E. (2011) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2011.01840.x · Cited by 49
Shim, J. C. (2004) · The Korean journal of pain · doi:10.3344/kjp.2004.17.s.s80 · Cited by 49
Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome
Roman, K., Done, J. D., Schaeffer, A. J., Murphy, S. F., & Thumbikat, P. (2014) · Pain · doi:10.1016/j.pain.2014.04.009 · Cited by 46
Wang, X., Liu, W., O’Donnell, M. A., Lutgendorf, S. K., Bradley, C. S., Schrepf, A., Liu, L., Kreder, K. J., & Luo, Y. (2016) · PLoS ONE · doi:10.1371/journal.pone.0168772 · Cited by 46
Is stress a trigger factor for migraine?
Schoonman, G. G., Evers, D. J., Ballieux, B. E. P. B., de Geus, E. J. C., de Kloet, E. R., Terwindt, G. M., van Dijk, J. G., & Ferrari, M. D. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.03.006 · Cited by 43
Coppens, E., Kempke, S., Wambeke, P. V., Claes, S. J., Morlion, B. J., Luyten, P., & Oudenhove, L. V. (2017) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000551 · Cited by 43
Sabharwal, R., Rasmussen, L., Sluka, K. A., & Chapleau, M. W. (2015) · Pain · doi:10.1097/j.pain.0000000000000330 · Cited by 41
Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells
Hanna‐Mitchell, A. T., Wolf‐Johnston, A., Roppolo, J. R., Buffington, T., & Birder, L. A. (2014) · Journal of Endocrinology · doi:10.1530/joe-13-0422 · Cited by 41
Effects of yogic intervention on pain scores and quality of life in females with chronic pelvic pain
Saxena, R., Gupta, M., Shankar, N., Jain, S., & Saxena, A. (2016) · International Journal of Yoga · doi:10.4103/0973-6131.186155 · Cited by 38
Stress enhances muscle nociceptor activity in the rat
Chen, X., Green, P. G., & Levine, J. D. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.04.020 · Cited by 37
Shyti, R., Eikermann‐Haerter, K., van Heiningen, S. H., Meijer, O. C., Ayata, C., Joëls, M., Ferrari, M. D., van den Maagdenberg, A. M. J. M., & Tolner, E. A. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.10.015 · Cited by 35
Mast Cell Activation in Sterile Bladder and Prostate Inflammation
Theoharides, T. C., Flaris, N. A., Cronin, C. T., Ucci, A. A., & Meares, E. M. (2009) · International Archives of Allergy and Applied Immunology · doi:10.1159/000235190 · Cited by 35
Recreational Physical Activity and Endometrioma Risk
Dhillon, P. K. (2003) · American Journal of Epidemiology · doi:10.1093/aje/kwg122 · Cited by 32
Till, S. R., Wahl, H. N., & As‐Sanie, S. (2017) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0000000000000376 · Cited by 31
A Systematic Review of Behavioral Headache Interventions With an Aerobic Exercise Component
Baillie, L. E., Gabriele, J. M., & Penzien, D. B. (2013) · Headache The Journal of Head and Face Pain · doi:10.1111/head.12204 · Cited by 30
Fuentes, I. M., Pierce, A. N., Silvestro, E. R. D., Maloney, M. O., & Christianson, J. A. (2018) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2017.00097 · Cited by 28
Self-citationOkragly, A. J., Morin, S. M., DeRosa, D. C., Martin, A. P., Johnson, K. W., Johnson, M. P., & Benschop, R. J. (2017) · Cephalalgia · doi:10.1177/0333102417740563 · Cited by 26
Fuentes, I. M., Pierce, A. N., O’Neil, P. T., & Christianson, J. A. (2015) · Journal of Visualized Experiments · doi:10.3791/53181 · Cited by 24
Self-citationFuentes, I. M., Walker, N. K., Pierce, A. N., Holt, B., Silvestro, E. R. D., & Christianson, J. A. (2016) · IBRO Reports · doi:10.1016/j.ibror.2016.07.001 · Cited by 24
Self-citationPsychological therapies (internet delivered) for the management of chronic pain in adults
Eccleston, C., Fisher, E., Craig, L., Duggan, G. B., Rosser, B. A., & Keogh, E. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd010152 · Cited by 21
Cognitive Behavioral Approaches to the Treatment of Pain
Waters, S. J., PhD, McKee, D. C., PhD, Keefe, A. F. J., & PhD (2025) · Psychopharmacology Bulletin · doi:10.64719/pb.4140 · Cited by 21
Exercise in Muscle Pain Disorders
Thompson, J. M. (2012) · PM&R · doi:10.1016/j.pmrj.2012.08.004 · Cited by 18
Mast cell profile in prostatic lesions.
Amir, T., Pai, R. R., & Raghuveer, C. V. (1998) · PubMed · Cited by 15
Cortisol and migraine. A systematic literature review
Lippi, G. (2017) · Ağrı - The Journal of The Turkish Society of Algology · doi:10.5505/agri.2017.25348 · Cited by 13
Keefe (1999) · doi:10.1002/1529-0131(199904)12:2
Flagged first, then by citations
3 of the 235 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- 2016, Statistics About Diabetes.
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Sorted by citations
The anatomy of pain and suffering in the brain and its clinical implications
Ridder, D. D., Adhia, D. B., & Vanneste, S. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.08.013 · Cited by 298
Reframing chronic pain as a disease, not a symptom: rationale and implications for pain management
Clauw, D. J., Essex, M. N., Pitman, V. W., & Jones, K. D. (2019) · Postgraduate Medicine · doi:10.1080/00325481.2019.1574403 · Cited by 300
Altered microbiome composition in individuals with fibromyalgia
Minerbi, A., Gonzalez, E., Brereton, N. J. B., Anjarkouchian, A., Dewar, K., Fitzcharles, M.-A., Chevalier, S., & Shir, Y. (2019) · Pain · doi:10.1097/j.pain.0000000000001640 · Cited by 220
Myofascial trigger points in migraine and tension-type headache
Do, T. P., Heldarskard, G. F., Kolding, L. T., Hvedstrup, J., & Schytz, H. (2018) · The Journal of Headache and Pain · doi:10.1186/s10194-018-0913-8 · Cited by 188
Central sensitization, chronic pain, and other symptoms: Better understanding, better management
Volcheck, M. M., Graham, S. M., Fleming, K. C., Mohabbat, A. B., & Luedtke, C. A. (2023) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.90a.22019 · Cited by 204
Metadata
- Authors
- Eller-Smith, O. C., Nicol, A. L., & Christianson, J. A.
- Affiliations
- University of Kansas Medical Center (US)
- Corresponding author
- Christianson, Julie A.
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2018-02-13
- Volume
- 12
- Pages
- 35-35
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC5816755
- OpenAlex
- W2793570991
- Cited by
- 227
- References
- 235
- Citations by year
- 2026: 31 · 2025: 24 · 2024: 20 · 2023: 31 · 2022: 31 · 2021: 31 · 2020: 26 · 2019: 23 · 2018: 10
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (DK099611, DK103872, GM123320, HD057850)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- fibromyalgia, chronic pelvic pain, migraine, temporomandibular disorders, central sensitization, HPA axis dysregulation, mast cells, hyperalgesic priming, wind-up, long-term potentiation, functional connectivity, non-pharmacological treatment, physical activity, cognitive behavioral therapy, comorbidities, quality of life
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