Skip to main content

Novel cytogenic and neurovascular niches due to blood–brain barrier compromise in the chronic pain brain



The mechanisms by which painful injuries are linked to the multitude of pain-related comorbidities and neuroplastic changes in the brain remain poorly understood. Here we propose a model that relies on epi-neuronal communication through the vascular system to effect various brain structures. Specifically, we hypothesize that the differential vulnerability of the blood–brain barrier (BBB) in different brain regions is associated with region-specific neuroplastic and neurovascular changes that are in turn associated with particular pain-related comorbidities.

Presentation of the hypothesis

We will present our hypothesis by focusing on two main points: (A) chronic pain (CP) is associated with differential BBB compromise. (B) Circulating mediators leaking through the BBB create cytogenic and neovascular niches associated with pain-related co-morbidities.

Testing the hypothesis

Pre-clinically, our hypothesis can be tested by observing, in parallel, BBB compromise, (neo)vascularization, neurogenesis, and their co-localization in animal pain models using imaging, microscopy, biochemical and other tools. Furthermore, the BBB can be experimentally damaged in specific brain regions, and the consequences of those lesions studied on nociception and associated comorbidities. Recently developed imaging techniques allow the analysis of blood brain barrier integrity in patients providing a route for translation of the laboratory findings. Though perhaps more limited, post-mortem examination of brains with available pain histories constitutes a second approach to addressing this hypothesis.

Implications of the hypothesis

Understanding changes in BBB permeability in chronic pain conditions has clear implications both for understanding the pathogenesis of chronic pain and for the design of novel treatments to prevent chronic pain and its consequences. More broadly, this hypothesis may help us to understand how peripheral injuries impact the brain via mechanisms other than commonly studied efferent sensory pathways.


Chronic pain (CP) is associated with a multitude of comorbidities, including cognitive impairment, memory deficits, depression, and anxiety [1], which further exacerbate disability and declining quality of life in CP patients. This implies the presence of neuroplastic changes in the brain. Indeed, such evidence is available from patients [2] and preclinical models [3, 4]. What remains less clear is the mechanism by which painful injuries result in changes that are separated in time and space from the initial injury, namely delayed changes in the brain. One attractive candidate set of mechanisms are the ascending and descending neuronal pathways connecting the periphery and the brain [5], but it is unclear whether these pathways can account for the host of central changes observed in CP patients [6]. Here we propose a complimentary mechanism that relies on epi-neuronal communication through the vascular system and its effect on various brain structures.

Although the blood–brain barrier (BBB) exists throughout the arborized levels of the vascular system in the central nervous system (CNS), there is scant basis for concluding that the brain is uniformly protected from BBB compromise. We therefore hypothesize that the differential vulnerability of the BBB in different brain regions is associated with region-specific neuroplastic and neurovascular changes in the brain that parallel particular pain-related comorbidities.

Presentation of the hypothesis

We will present our hypothesis in the following main points:

  1. (a)

    CP is associated with differential BBB compromise.

BBB integrity is altered in various painful clinical conditions [79] and in pre-clinical models of pain [1013]. Most of the preclinical studies involve models of inflammatory pain, and the breakdown of tight junctions (TJ) has been implicated in the observed BBB compromise. This possibility is exemplified by a recent study showing that substance P, a pro-inflammatory mediator with well-established roles in nociception [14], activates brain microvascular endothelial cells. This leads to secretion of tumor necrosis factor alpha (TNFα) and angiopoietin-2 thus changing the localization and distribution of TJ protein zonula occludins-1 and claudin-5 structures as well as increasing permeability of brain microvascular endothelial cells [15]. Moreover, it is well-established that glia play a pivotal role in BBB maintenance [16]. Glial activation and the production of pro-inflammatory cytokines including interleukin-1 beta and TNFα has been demonstrated in many CP models, and these mediators may enhance BBB permeability [17] (Fig. 1).

Fig. 1
figure 1

Summary of the hypothesis. AutoAB autoantibody, ICAM intercellular adhesion molecule, IL interleukin, SP substance P, TJ tight junction, TNFα tumor necrosis factor alpha

Besides local immune response in the form of glial activation that might parallel CP in various brain regions [18], the pathological consequences of BBB compromise may result from the disruption of relative “immune quiescence.” The brain is normally accessible only to small, lipid-soluble molecules [19], but in pain states, additional circulating mediators can access it. For instance, in models of surgical trauma, hippocampal BBB disruption and increased levels of systemic cytokines accompany significant neurocognitive impairment [20, 21], potentially through an interleukin-1-beta-dependent mechanism [22]. Circulating autoantibodies could also be involved since they are elevated in various pain conditions including complex regional pain syndrome [23] and back pain [24]. While there is little specific evidence of pain-related brain autoantibody infiltration, this may be a reasonable hypothesis based on observations of such infiltration in conditions such as systemic lupus erythematosus [25] and stroke [26].

  1. (b)

    Circulating mediators leaking through the BBB create cytogenic and neovascular niches associated with pain-related co-morbidities.

Cytogenic changes may occur in CP in the form of hippocampal neurogenesis in neonates [27] and adults [28]; furthermore CP is associated with reversible anatomical and epigenetic changes in the prefrontal cortex in humans [2] and mice [4]. Based on previous publications [713], we hypothesize that this is partially due to BBB compromise throughout some of the brain vasculature, thereby resulting in the aberrant distribution of mediators that are responsible for cytogenesis.

The bidirectional regulation of neuronal and vascular growth and barrier formation has been investigated in greatest detail during development [29]. Less is known about these processes in the adult brain where plasticity is observed, though our knowledge base is expanding rapidly. For example, local vasculature with a leaky BBB can regulate adult neurogenesis [30] and experience-dependent angiogenesis and changes in neurovascular structure occur in the somatosensory cortex [31] (though pain as an experience was not carefully evaluated). Neurovascular changes were also found to regulate learning and memory in the Morris water maze [32]. These observations are significant as angiogenesis is a localized process during which BBB integrity may be compromised due to the existence of an incomplete epithelium [33] (Fig. 2). We hypothesize that, similar to the observations related to CNS formation, memory formation and experience-related neuroplasticity, CP alters regional vascular structure [34] and BBB permeability. This provides a pathway for the direct communication between the systemic circulation and the brain.

Fig. 2
figure 2

Vicious cycle of BBB compromise and cytogenesis/neovascularization contributes to pain-associated neuroplasticity. BBB blood–brain barrier

Testing the hypothesis

Our hypothesis can be tested in both preclinical and clinical settings. In animal models of pain, the existence of BBB compromise, (neo)vascularization and neurogenesis (and their localization relative to one another) can be accomplished by using Evan’s blue/TJ protein quantification/IgG and IgM quantification, India ink-gelatin perfusion, and BrdU staining, respectively. Additionally, undertaking longitudinal studies would be crucial in distinguishing between transient changes after injury and the chronic ones that parallel the timecourse of development of comorbidities in addition to teasing apart cellular proliferation from cellular survival. The advent of sophisticated next-generation microscopy tools [35] could potentially help visualize the connection of astrocytic podocytes to blood vessels in in vitro preparations, and could even be employed to test the effect of different mediators (including those elevated in CP) in the astrocyte-blood vessel preparations. Besides studying the physical integrity of the BBB, its biochemical barrier functionality can be studied in vitro, including the examination of metabolizing enzymes and ATP-driven efflux pumps [36]. Furthermore, the BBB can be experimentally damaged in different brain structures and its long-term effects studied on pain-associated comorbidities following the induction of CP. Such studies could tease apart the effects of BBB compromise and those of circulating mediators in the intact BBB. For instance, pre-existing circulating autoantibodies were shown to exert either beneficial or detrimental effects in ischemic brain injury, depending on the integrity of the BBB [26].

The postmortem study of CP brains could yield equally important information: In suicide completers, for example, a dysfunction in astrocyte connexins is observed in the dorsolateral prefrontal cortex [37], potentially due to a weakened BBB [38]. Similarly, in vivo imaging of BBB disruption in CP patients would be crucial [39], particularly if the association between BBB compromise and cerebral blood flow, pain score, and observed comorbidities is examined in longitudinal timecourse studies.

Implications of the hypothesis

Understanding changes in BBB permeability in CP conditions has clear implications both in the imaging (delivery of contrast agents) and treatment (delivery of therapeutic agents) of painful conditions. For instance, changes observed by brain imaging could be confounded by BBB compromise and anti-angiogenic agents could be considered potential therapeutic targets in instances where regional leak of the BBB due to neurovascular changes is observed.

It should be recognized that the current hypothesis does not exclude any alternative paths through which immune cells traffic through the CNS that might also modulate chronic pain. For instance, a recent publication showed the existence of a functional CNS lymphatic system, further challenging the long-held assumptions in CNS neuro-immunology [40].





central nervous system


chronic pain


tight junction


tumor necrosis factor alpha


  1. 1.

    Sharp J, Keefe B. Psychiatry in chronic pain: a review and update. Curr Psychiatry Rep. 2005;7:213–9.

    Article  PubMed  Google Scholar 

  2. 2.

    Seminowicz DA, Wideman TH, Naso L, Hatami-Khoroushahi Z, Fallatah S, Ware MA, Jarzem P, Bushnell MC, Shir Y, Ouellet JA, Stone LS. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci Off J Soc Neurosci. 2011;31:7540–50.

    CAS  Article  Google Scholar 

  3. 3.

    Tajerian M, Leu D, Zou Y, Sahbaie P, Li W, Khan H, Hsu V, Kingery W, Huang TT, Becerra L, Clark JD. Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome. Anesthesiology. 2014;121:852–65.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  4. 4.

    Tajerian M, Alvarado S, Millecamps M, Vachon P, Crosby C, Bushnell MC, Szyf M, Stone LS. Peripheral nerve injury is associated with chronic, reversible changes in global DNA methylation in the mouse prefrontal cortex. PLoS One. 2013;8:e55259.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. 5.

    Chen T, Koga K, Descalzi G, Qiu S, Wang J, Zhang LS, Zhang ZJ, He XB, Qin X, Xu FQ, et al. Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury. Mol Pain. 2014;10:33.

    PubMed Central  Article  PubMed  Google Scholar 

  6. 6.

    Baliki MN, Apkarian AV. Nociception, pain, negative moods, and behavior selection. Neuron. 2015;87:474–91.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Chodobski A, Zink BJ, Szmydynger-Chodobska J. Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res. 2011;2:492–516.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Sanchez-del-Rio M, Reuter U. Migraine aura: new information on underlying mechanisms. Curr Opin Neurol. 2004;17:289–93.

    Article  PubMed  Google Scholar 

  9. 9.

    Mogi M, Horiuchi M. Neurovascular coupling in cognitive impairment associated with diabetes mellitus. Circ J Off J Jpn Circ Soc. 2011;75:1042–8.

    CAS  Google Scholar 

  10. 10.

    Huber JD, Witt KA, Hom S, Egleton RD, Mark KS, Davis TP. Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol. 2001;280:H1241–8.

    CAS  PubMed  Google Scholar 

  11. 11.

    Brooks TA, Hawkins BT, Huber JD, Egleton RD, Davis TP. Chronic inflammatory pain leads to increased blood–brain barrier permeability and tight junction protein alterations. Am J Physiol Heart Circ Physiol. 2005;289:H738–43.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Huber JD, Hau VS, Borg L, Campos CR, Egleton RD, Davis TP. Blood–brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol. 2002;283:H1531–7.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Huber JD, Campos CR, Mark KS, Davis TP. Alterations in blood–brain barrier ICAM-1 expression and brain microglial activation after lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol. 2006;290:H732–40.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Rittner HL, Brack A, Stein C. Pain and the immune system. Br J Anaesth. 2008;101:40–4.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Rodriguez PL, Jiang S, Fu Y, Avraham S, Avraham HK. The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. Int J Cancer. 2014;134:1034–44.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Alvarez JI, Katayama T, Prat A. Glial influence on the blood brain barrier. Glia. 2013;61:1939–58.

    PubMed Central  Article  PubMed  Google Scholar 

  17. 17.

    Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A. Interleukin-1beta induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PLoS One. 2014;9:e110024.

    PubMed Central  Article  PubMed  Google Scholar 

  18. 18.

    Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji RR, et al. Evidence for brain glial activation in chronic pain patients. Brain J Neurol. 2015;138:604–15.

    Article  Google Scholar 

  19. 19.

    Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37:13–25.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    He HJ, Wang Y, Le Y, Duan KM, Yan XB, Liao Q, Liao Y, Tong JB, Terrando N, Ouyang W. Surgery upregulates high mobility group box-1 and disrupts the blood–brain barrier causing cognitive dysfunction in aged rats. CNS Neurosci Ther. 2012;18:994–1002.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Feldmann M, Jonsson Fagerlund M, Charo IF, Akassoglou K, Maze M. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011;70:986–95.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  22. 22.

    Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68:360–8.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Dirckx M, Schreurs MW, de Mos M, Stronks DL, Huygen FJ. The prevalence of autoantibodies in complex regional pain syndrome type I. Mediat Inflamm. 2015;2015:718201.

    Article  Google Scholar 

  24. 24.

    Capossela S, Schlafli P, Bertolo A, Janner T, Stadler BM, Potzel T, Baur M, Stoyanov JV. Degenerated human intervertebral discs contain autoantibodies against extracellular matrix proteins. Eur Cells Mater. 2014;27:251–63 (discussion 263).

    CAS  Google Scholar 

  25. 25.

    Kelly-Worden M, Hammer L, Gebhard R, Schrader L, Griffin M, Cooper D. Anti-nuclear antibodies positive serum from systemic lupus erythematosus patients promotes cardiovascular manifestations and the presence of human antibody in the brain. J Pharm Bioallied Sci. 2014;6:198–204.

    PubMed Central  Article  PubMed  Google Scholar 

  26. 26.

    Zerche M, Weissenborn K, Ott C, Dere E, Asif AR, Worthmann H, Hassouna I, Rentzsch K, Tryc AB, Dahm L, et al. Preexisting serum autoantibodies against the NMDAR subunit NR1 modulate evolution of lesion size in acute ischemic stroke. Stroke J Cereb Circ. 2015;46:1180–6.

    CAS  Article  Google Scholar 

  27. 27.

    Leslie AT, Akers KG, Martinez-Canabal A, Mello LE, Covolan L, Guinsburg R. Neonatal inflammatory pain increases hippocampal neurogenesis in rat pups. Neurosci Lett. 2011;501:78–82.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Apkarian AV, Mutso AA, Centeno MV, Kan L, Wu M, Levinstein M, Banisadr G, Gobeske KT, Miller RJ, Radulovic J, et al. Role of adult hippocampal neurogenesis in persistent pain. Pain. 2015. doi:10.1097/j.pain.0000000000000332.

    Google Scholar 

  29. 29.

    Stolp HB, Molnar Z. Neurogenic niches in the brain: help and hindrance of the barrier systems. Front Neurosci. 2015;9:20.

    PubMed Central  Article  PubMed  Google Scholar 

  30. 30.

    Yuan TF, Liang YX, Tay D, So KF, Ellis-Behnke R. Specialized vasculature in the rostral migratory stream as a neurogenic niche and scaffold for neuroblast migration. Cell Transplant. 2015;24:377–90.

    Article  PubMed  Google Scholar 

  31. 31.

    Kole K. Experience dependent plasticity of the Neurovasculature. J Neurophysiol. 2014;114:2077–9.

    Article  PubMed  Google Scholar 

  32. 32.

    Kerr AL, Steuer EL, Pochtarev V, Swain RA. Angiogenesis but not neurogenesis is critical for normal learning and memory acquisition. Neuroscience. 2010;171:214–26.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Tanifum EA, Starosolski ZA, Fowler SW, Jankowsky JL, Annapragada AV. Cerebral vascular leak in a mouse model of amyloid neuropathology. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2014;34:1646–54.

    CAS  Article  Google Scholar 

  34. 34.

    Alvarado S, Tajerian M, Millecamps M, Suderman M, Stone LS, Szyf M. Peripheral nerve injury is accompanied by chronic transcriptome-wide changes in the mouse prefrontal cortex. Mol Pain. 2013;9:21.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  35. 35.

    Cotte Y, Toy F, Jourdain P, Pavillon N, Boss D, Magistretti P, Marquet P, Depeursinge C. Marker-free phase nanoscopy. Nat Photonics. 2013;7:113–7.

    CAS  Article  Google Scholar 

  36. 36.

    Miller DS, Cannon RE. Signaling pathways that regulate basal ABC transporter activity at the blood- brain barrier. Curr Pharm Des. 2014;20:1463–71.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Ernst C, Nagy C, Kim S, Yang JP, Deng X, Hellstrom IC, Choi KH, Gershenfeld H, Meaney MJ, Turecki G. Dysfunction of astrocyte connexins 30 and 43 in dorsal lateral prefrontal cortex of suicide completers. Biol Psychiatry. 2011;70:312–9.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Ezan P, Andre P, Cisternino S, Saubamea B, Boulay AC, Doutremer S, Thomas MA, Quenech’du N, Giaume C, Cohen-Salmon M. Deletion of astroglial connexins weakens the blood-brain barrier. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2012;32:1457–67.

    CAS  Article  Google Scholar 

  39. 39.

    Heye AK, Culling RD, Valdes Hernandez Mdel C, Thrippleton MJ, Wardlaw JM. Assessment of blood–brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review. NeuroImage Clin. 2014;6:262–74.

    PubMed Central  Article  PubMed  Google Scholar 

  40. 40.

    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–41.

    CAS  Article  PubMed  Google Scholar 

Download references

Authors’ contributions

MT, JDC: wrote the manuscript. Both authors read and approved the final manuscript.


The authors would like to thank Dr. Sebastian G. Alvarado for careful review of the manuscript. J. D. Clark received salary support from the Department of Veterans Affairs Merit Review Grant 1I01RX001475, and the NIH/NINDS NS072143. MT was supported by NIH Grant 5T32DA035165-02.

Competing interests

The authors declare no competing interests.

Author information



Corresponding author

Correspondence to Maral Tajerian.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tajerian, M., Clark, J.D. Novel cytogenic and neurovascular niches due to blood–brain barrier compromise in the chronic pain brain. Mol Pain 11, 63 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Blood–brain-barrier
  • Chronic pain
  • Neuroinflammation
  • Neurogenesis
  • Neovascularization
  • Pain-related brain plasticity
  • Pain-related co-morbidities