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Does inflammation have a role in migraine?


Migraine is a prevalent disorder, affecting 15.1% of the world’s population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develop chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, we review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. We present evidence from preclinical research that supports this view and discuss the implications for migraine therapy.

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Fig. 1: Migraine progression and chronification.
Fig. 2: Effects of dural CFA administration on the trigeminal ganglion.
Fig. 3: Effects of TMJ CFA injection on the trigeminal ganglion.


  1. 1.

    GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1211–1259 (2017).

    Google Scholar 

  2. 2.

    Goadsby, P. J. et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol. Rev. 97, 553–622 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Schulte, L. H. & May, A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139, 1987–1993 (2016).

    PubMed  Google Scholar 

  4. 4.

    Charles, A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 17, 174–182 (2018).

    CAS  PubMed  Google Scholar 

  5. 5.

    Edvinsson, L. & Uddman, R. Neurobiology in primary headaches. Brain Res. Brain Res. Rev. 48, 438–456 (2005).

    PubMed  Google Scholar 

  6. 6.

    Edvinsson, L. Functional role of perivascular peptides in the control of cerebral circulation. Trends Neurosci. 8, 126–131 (1985).

    CAS  Google Scholar 

  7. 7.

    Edvinsson, L., Haanes, K. A., Warfvinge, K. & Krause, D. N. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat. Rev. Neurol. 14, 338–350 (2018).

    CAS  PubMed  Google Scholar 

  8. 8.

    Pietrobon, D. & Moskowitz, M. A. Pathophysiology of migraine. Annu. Rev. Physiol. 75, 365–391 (2013).

    CAS  PubMed  Google Scholar 

  9. 9.

    Peroutka, S. J. Neurogenic inflammation and migraine: implications for the therapeutics. Mol. Interv. 5, 304–311 (2005).

    CAS  PubMed  Google Scholar 

  10. 10.

    Goldstein, D. J. et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 21, 102–106 (2001).

    CAS  PubMed  Google Scholar 

  11. 11.

    Diener, H. C. & RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23, 183–185 (2003).

    PubMed  Google Scholar 

  12. 12.

    Goldstein, D. J. et al. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17, 785–790 (1997).

    CAS  PubMed  Google Scholar 

  13. 13.

    Serrano, D. et al. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treatment and clinical trial design. J. Headache Pain 18, 101 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lipton, R. B. et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68, 343–349 (2007).

    CAS  PubMed  Google Scholar 

  15. 15.

    Lipton, R. B., Manack Adams, A., Buse, D. C., Fanning, K. M. & Reed, M. L. A comparison of the Chronic Migraine Epidemiology and Outcomes (CaMEO) study and American Migraine Prevalence and Prevention (AMPP) study: demographics and headache-related disability. Headache 56, 1280–1289 (2016).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Moskowitz, M. A. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol. Sci. 13, 307–311 (1992).

    CAS  PubMed  Google Scholar 

  17. 17.

    Bolay, H. et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8, 136–142 (2002).

    CAS  PubMed  Google Scholar 

  18. 18.

    Zhang, X. et al. Activation of central trigeminovascular neurons by cortical spreading depression. Ann. Neurol. 69, 855–865 (2011).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Williamson, D. J., Hargreaves, R. J., Hill, R. G. & Shepheard, S. L. Intravital microscope studies on the effects of neurokinin agonists and calcitonin gene-related peptide on dural vessel diameter in the anaesthetized rat. Cephalalgia 17, 518–524 (1997).

    CAS  PubMed  Google Scholar 

  21. 21.

    Edvinsson, L. et al. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. Cephalalgia 30, 1233–1240 (2010).

    PubMed  Google Scholar 

  22. 22.

    Jansen, I. et al. Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries. Peptides 13, 527–536 (1992).

    CAS  PubMed  Google Scholar 

  23. 23.

    Feniuk, W., Humphrey, P. P., Perren, M. J., Connor, H. E. & Whalley, E. T. Rationale for the use of 5-HT1-like agonists in the treatment of migraine. J. Neurol. 238 (Suppl. 1), S57–S61 (1991).

    PubMed  Google Scholar 

  24. 24.

    Khan, S. et al. Meningeal contribution to migraine pain: a magnetic resonance angiography study. Brain 142, 93–102 (2019).

    PubMed  Google Scholar 

  25. 25.

    Amin, F. M. et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 12, 454–461 (2013).

    PubMed  Google Scholar 

  26. 26.

    Goadsby, P. J. & Edvinsson, L. Joint 1994 Wolff Award Presentation. Peripheral and central trigeminovascular activation in cat is blocked by the serotonin (5HT)-1D receptor agonist 311C90. Headache 34, 394–399 (1994).

    CAS  PubMed  Google Scholar 

  27. 27.

    Amrutkar, D. V. et al. mRNA expression of 5-hydroxytryptamine 1B, 1D, and 1F receptors and their role in controlling the release of calcitonin gene-related peptide in the rat trigeminovascular system. Pain 153, 830–838 (2012).

    CAS  PubMed  Google Scholar 

  28. 28.

    Gupta, S. et al. Intravital microscopy on a closed cranial window in mice: a model to study trigeminovascular mechanisms involved in migraine. Cephalalgia 26, 1294–1303 (2006).

    CAS  PubMed  Google Scholar 

  29. 29.

    Goadsby, P. J. & Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56 (1993).

    CAS  PubMed  Google Scholar 

  30. 30.

    Markowitz, S., Saito, K. & Moskowitz, M. A. Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J. Neurosci. 7, 4129–4136 (1987).

    CAS  PubMed  Google Scholar 

  31. 31.

    Markowitz, S., Saito, K. & Moskowitz, M. A. Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache. Cephalalgia 8, 83–91 (1988).

    CAS  PubMed  Google Scholar 

  32. 32.

    Buzzi, M. G., Moskowitz, M. A., Peroutka, S. J. & Byun, B. Further characterization of the putative 5-HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater. Br. J. Pharmacol. 103, 1421–1428 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Knotkova, H. & Pappagallo, M. Imaging intracranial plasma extravasation in a migraine patient: a case report. Pain Med. 8, 383–387 (2007).

    PubMed  Google Scholar 

  34. 34.

    May, A. & Goadsby, P. J. Substance P receptor antagonists in the therapy of migraine. Expert Opin. Investig. Drugs 10, 673–678 (2001).

    CAS  PubMed  Google Scholar 

  35. 35.

    Roon, K. I. et al. No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized, double-blind, placebo-controlled clinical trials. Ann. Neurol. 47, 238–241 (2000).

    CAS  PubMed  Google Scholar 

  36. 36.

    Earl, N. L., McDonald, S. A. & Lowy, M. T. Efficacy and tolerability of the neurogenic inflammation inhibitor, 4991W93, in the acute treatment of migraine. Cephalalgia 19, 357 (1999).

    Google Scholar 

  37. 37.

    Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990).

    CAS  PubMed  Google Scholar 

  38. 38.

    Levy, D., Burstein, R. & Strassman, A. M. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann. Neurol. 58, 698–705 (2005).

    CAS  PubMed  Google Scholar 

  39. 39.

    Edvinsson, L., Cervos-Navarro, J., Larsson, L. I., Owman, C. & Ronnberg, A. L. Regional distribution of mast cells containing histamine, dopamine, or 5-hydroxytryptamine in the mammalian brain. Neurology 27, 878–883 (1977).

    CAS  PubMed  Google Scholar 

  40. 40.

    MacKenzie, E. T., Edvinsson, L. & Scatton, B. Functional bases for a central serotonergic involvement in classic migraine: a speculative view. Cephalalgia 5, 69–78 (1985).

    CAS  PubMed  Google Scholar 

  41. 41.

    Edvinsson, L. & Uddman, R. Adrenergic, cholinergic and peptidergic nerve fibres in dura mater—involvement in headache? Cephalalgia 1, 175–179 (1981).

    CAS  PubMed  Google Scholar 

  42. 42.

    Edvinsson, L., Ekman, R., Jansen, I., McCulloch, J. & Uddman, R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J. Cereb. Blood Flow Metab. 7, 720–728 (1987).

    CAS  PubMed  Google Scholar 

  43. 43.

    Eftekhari, S., Warfvinge, K., Blixt, F. W. & Edvinsson, L. Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J. Pain 14, 1289–1303 (2013).

    CAS  PubMed  Google Scholar 

  44. 44.

    Ottosson, A. & Edvinsson, L. Release of histamine from dural mast cells by substance P and calcitonin gene-related peptide. Cephalalgia 17, 166–174 (1997).

    CAS  PubMed  Google Scholar 

  45. 45.

    Matsuda, M., Huh, Y. & Ji, R. R. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J. Anesth. 33, 131–139 (2019).

    PubMed  Google Scholar 

  46. 46.

    Ji, R. R., Kohno, T., Moore, K. A. & Woolf, C. J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 26, 696–705 (2003).

    CAS  PubMed  Google Scholar 

  47. 47.

    Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Ji, R. R., Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Wen, Y. R. et al. Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia. Anesthesiology 110, 155–165 (2009).

    CAS  PubMed  Google Scholar 

  50. 50.

    Kobayashi, K. et al. P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J. Neurosci. 28, 2892–2902 (2008).

    CAS  PubMed  Google Scholar 

  51. 51.

    Jin, S. X., Zhuang, Z. Y., Woolf, C. J. & Ji, R. R. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J. Neurosci. 23, 4017–4022 (2003).

    CAS  PubMed  Google Scholar 

  52. 52.

    Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S. & Inoue, K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45, 89–95 (2004).

    PubMed  Google Scholar 

  53. 53.

    Ji, R. R., Nackley, A., Huh, Y., Terrando, N. & Maixner, W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129, 343–366 (2018).

    PubMed  Google Scholar 

  54. 54.

    Christianson, C. A. et al. Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 152, 2881–2891 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Johnson, K. W. & Bolay, H. in The Headaches 3rd edn (eds Olesen, J. et al.) 309–319 (Lipincott Williams & Wilkins, 2006).

  56. 56.

    Covelli, V. et al. Are TNF-alpha and IL-1 beta relevant in the pathogenesis of migraine without aura? Acta Neurol. (Napoli) 13, 205–211 (1991).

    CAS  Google Scholar 

  57. 57.

    Perini, F. et al. Plasma cytokine levels in migraineurs and controls. Headache 45, 926–931 (2005).

    PubMed  Google Scholar 

  58. 58.

    Franceschini, A. et al. TNFalpha levels and macrophages expression reflect an inflammatory potential of trigeminal ganglia in a mouse model of familial hemiplegic migraine. PLOS ONE 8, e52394 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Tanure, M. T., Gomez, R. S., Hurtado, R. C., Teixeira, A. L. & Domingues, R. B. Increased serum levels of brain-derived neurotropic factor during migraine attacks: a pilot study. J. Headache Pain 11, 427–430 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Yucel, M., Kotan, D., Gurol Ciftci, G., Ciftci, I. H. & Cikriklar, H. I. Serum levels of endocan, claudin-5 and cytokines in migraine. Eur. Rev. Med. Pharmacol. Sci. 20, 930–936 (2016).

    CAS  PubMed  Google Scholar 

  61. 61.

    Sarchielli, P. et al. Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally. Headache 46, 200–207 (2006).

    PubMed  Google Scholar 

  62. 62.

    Hassett, B. et al. Manufacturing history of etanercept (Enbrel®): Consistency of product quality through major process revisions. MAbs 10, 159–165 (2018).

    CAS  PubMed  Google Scholar 

  63. 63.

    de Vries, H. E. et al. The influence of cytokines on the integrity of the blood–brain barrier in vitro. J. Neuroimmunol. 64, 37–43 (1996).

    PubMed  Google Scholar 

  64. 64.

    Laflamme, N. & Rivest, S. Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. J. Neurochem. 73, 309–321 (1999).

    CAS  PubMed  Google Scholar 

  65. 65.

    Cottier, K. E. et al. Loss of blood–brain barrier integrity in a KCl-induced model of episodic headache enhances CNS drug delivery. eNeuro (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Fried, N. T., Maxwell, C. R., Elliott, M. B. & Oshinsky, M. L. Region-specific disruption of the blood–brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia. Cephalalgia 38, 674–689 (2018).

    PubMed  Google Scholar 

  67. 67.

    Edvinsson, L. & Tfelt-Hansen, P. The blood–brain barrier in migraine treatment. Cephalalgia 28, 1245–1258 (2008).

    CAS  PubMed  Google Scholar 

  68. 68.

    Hougaard, A. et al. Increased brainstem perfusion, but no blood–brain barrier disruption, during attacks of migraine with aura. Brain 140, 1633–1642 (2017).

    PubMed  Google Scholar 

  69. 69.

    Schankin, C. J. et al. Ictal lack of binding to brain parenchyma suggests integrity of the blood–brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine. Brain 139, 1994–2001 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Amin, F. M. et al. Intact blood–brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. Eur. J. Neurol. 24, 1116–1124 (2017).

    CAS  PubMed  Google Scholar 

  71. 71.

    Lundblad, C., Haanes, K. A., Grande, G. & Edvinsson, L. Experimental inflammation following dural application of complete Freund’s adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. J. Headache Pain 16, 91 (2015).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    May, A. Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol. Sci. 38, 125–130 (2017).

    PubMed  Google Scholar 

  73. 73.

    Schulte, L. H., Jurgens, T. P. & May, A. Photo-, osmo- and phonophobia in the premonitory phase of migraine: mistaking symptoms for triggers? J. Headache Pain 16, 14 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. 74.

    Charbit, A. R., Akerman, S. & Goadsby, P. J. Dopamine: what’s new in migraine? Curr. Opin. Neurol. 23, 275–281 (2010).

    CAS  PubMed  Google Scholar 

  75. 75.

    Alstadhaug, K., Salvesen, R. & Bekkelund, S. Insomnia and circadian variation of attacks in episodic migraine. Headache 47, 1184–1188 (2007).

    PubMed  Google Scholar 

  76. 76.

    Silberstein, S. & Merriam, G. Sex hormones and headache 1999 (menstrual migraine). Neurology 53, S3–S13 (1999).

    CAS  PubMed  Google Scholar 

  77. 77.

    Khor, S. & Cai, D. Hypothalamic and inflammatory basis of hypertension. Clin. Sci. 131, 211–223 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Posey, K. A. et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 296, E1003–E1012 (2009).

    CAS  PubMed  Google Scholar 

  79. 79.

    Purkayastha, S., Zhang, G. & Cai, D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-beta and NF-kappaB. Nat. Med. 17, 883–887 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Arruda, A. P. et al. Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology 152, 1314–1326 (2011).

    CAS  PubMed  Google Scholar 

  81. 81.

    Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    CAS  PubMed  Google Scholar 

  82. 82.

    Loggia, M. L. et al. Evidence for brain glial activation in chronic pain patients. Brain 138, 604–615 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Vecsei, L., Majlath, Z., Balog, A. & Tajti, J. Drug targets of migraine and neuropathy: treatment of hyperexcitability. CNS Neurol. Disord. Drug Targets 14, 664–676 (2015).

    CAS  PubMed  Google Scholar 

  84. 84.

    Boyer, N., Dallel, R., Artola, A. & Monconduit, L. General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. Pain 155, 1196–1205 (2014).

    PubMed  Google Scholar 

  85. 85.

    Oshinsky, M. L. Sensitization and ongoing activation in the trigeminal nucleus caudalis. Pain 155, 1181–1182 (2014).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Oka, T., Aou, S. & Hori, T. Intracerebroventricular injection of interleukin-1 beta enhances nociceptive neuronal responses of the trigeminal nucleus caudalis in rats. Brain Res. 656, 236–244 (1994).

    CAS  PubMed  Google Scholar 

  87. 87.

    Manack, A. N., Buse, D. C. & Lipton, R. B. Chronic migraine: epidemiology and disease burden. Curr. Pain Headache Rep. 15, 70–78 (2011).

    PubMed  Google Scholar 

  88. 88.

    Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia 38, 1–211 (2018).

    Google Scholar 

  89. 89.

    Nakamura-Craig, M. & Gill, B. K. Effect of neurokinin A, substance P and calcitonin gene related peptide in peripheral hyperalgesia in the rat paw. Neurosci. Lett. 124, 49–51 (1991).

    CAS  PubMed  Google Scholar 

  90. 90.

    Birrell, G. J., McQueen, D. S., Iggo, A., Coleman, R. A. & Grubb, B. D. PGI2-induced activation and sensitization of articular mechanonociceptors. Neurosci. Lett. 124, 5–8 (1991).

    CAS  PubMed  Google Scholar 

  91. 91.

    Wang, H., Ehnert, C., Brenner, G. J. & Woolf, C. J. Bradykinin and peripheral sensitization. Biol. Chem. 387, 11–14 (2006).

    CAS  PubMed  Google Scholar 

  92. 92.

    Schaible, H. G. & Schmidt, R. F. Excitation and sensitization of fine articular afferents from cat’s knee joint by prostaglandin E2. J. Physiol. 403, 91–104 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Hurley, J. H., Kunkler, P. E., Zhang, L., Knopp, K. L. & Oxford, G. S. Role of intraganglionic transmission in the trigeminovascular pathway. Mol. Pain 15, 1744806919836570 (2019).

    PubMed  PubMed Central  Google Scholar 

  94. 94.

    Natura, G., von Banchet, G. S. & Schaible, H. G. Calcitonin gene-related peptide enhances TTX-resistant sodium currents in cultured dorsal root ganglion neurons from adult rats. Pain 116, 194–204 (2005).

    CAS  PubMed  Google Scholar 

  95. 95.

    Haanes, K. A. & Edvinsson, L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs (2019).

    Article  PubMed  Google Scholar 

  96. 96.

    Eftekhari, S. et al. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience 169, 683–696 (2010).

    CAS  PubMed  Google Scholar 

  97. 97.

    Afroz, S. et al. CGRP induces differential regulation of cytokines from satellite glial cells in trigeminal ganglia and orofacial nociception. Int. J. Mol. Sci. 20, E711 (2019).

    PubMed  Google Scholar 

  98. 98.

    Walker, C. S., Raddant, A. C., Woolley, M. J., Russo, A. F. & Hay, D. L. CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia 38, 437–451 (2018).

    PubMed  Google Scholar 

  99. 99.

    Melo-Carrillo, A. et al. Selective inhibition of trigeminovascular neurons by fremanezumab: a humanized monoclonal anti-CGRP antibody. J. Neurosci. 37, 7149–7163 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Melo-Carrillo, A. et al. Fremanezumab-A humanized monoclonal anti-CGRP antibody-inhibits thinly myelinated (Adelta) but not unmyelinated (C) meningeal nociceptors. J. Neurosci. 37, 10587–10596 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Xanthos, D. N. & Sandkuhler, J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43–53 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Ulrich-Lai, Y. M., Flores, C. M., Harding-Rose, C. A., Goodis, H. E. & Hargreaves, K. M. Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from rat trigeminal ganglion: evidence for intraganglionic neurotransmission. Pain 91, 219–226 (2001).

    CAS  PubMed  Google Scholar 

  103. 103.

    Shafer, D. M., Assael, L., White, L. B. & Rossomando, E. F. Tumor necrosis factor-alpha as a biochemical marker of pain and outcome in temporomandibular joints with internal derangements. J. Oral Maxillofac. Surg. 52, 786–791 (1994).

    CAS  PubMed  Google Scholar 

  104. 104.

    Kubota, E., Kubota, T., Matsumoto, J., Shibata, T. & Murakami, K. I. Synovial fluid cytokines and proteinases as markers of temporomandibular joint disease. J. Oral Maxillofac. Surg. 56, 192–198 (1998).

    CAS  PubMed  Google Scholar 

  105. 105.

    Russo, A. F., Kuburas, A., Kaiser, E. A., Raddant, A. C. & Recober, A. A potential preclinical migraine model: CGRP-sensitized mice. Mol. Cell Pharmacol. 1, 264–270 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Kristiansen, K. A. & Edvinsson, L. Neurogenic inflammation: a study of rat trigeminal ganglion. J. Headache Pain 11, 485–495 (2010).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Kuris, A. et al. Enhanced expression of CGRP in rat trigeminal ganglion neurons during cell and organ culture. Brain Res. 1173, 6–13 (2007).

    CAS  PubMed  Google Scholar 

  108. 108.

    Tajti, J., Kuris, A., Vecsei, L., Xu, C. B. & Edvinsson, L. Organ culture of the trigeminal ganglion induces enhanced expression of calcitonin gene-related peptide via activation of extracellular signal-regulated protein kinase 1/2. Cephalalgia 31, 95–105 (2011).

    PubMed  Google Scholar 

  109. 109.

    Li, Y. et al. Capsaicin-induced activation of ERK1/2 and its involvement in GAP-43 expression and CGRP depletion in organotypically cultured DRG neurons. Cell. Mol. Neurobiol. 33, 433–441 (2013).

    PubMed  Google Scholar 

  110. 110.

    Csati, A. et al. Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion. J. Headache Pain 16, 99 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Marbach, J. J. & Levitt, M. Erythrocyte catechol-O-methyltransferase activity in facial pain patients. J. Dent. Res. 55, 711 (1976).

    CAS  PubMed  Google Scholar 

  112. 112.

    Mannisto, P. T. & Kaakkola, S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol. Rev. 51, 593–628 (1999).

    CAS  PubMed  Google Scholar 

  113. 113.

    Lotta, T. et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34, 4202–4210 (1995).

    CAS  PubMed  Google Scholar 

  114. 114.

    Yamakita, S. et al. Synergistic activation of ERK1/2 between A-fiber neurons and glial cells in the DRG contributes to pain hypersensitivity after tissue injury. Mol. Pain 14, 1744806918767508 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Takeda, M. et al. Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation. Pain 129, 155–166 (2007).

    CAS  PubMed  Google Scholar 

  116. 116.

    Takeda, M., Takahashi, M. & Matsumoto, S. Contribution of activated interleukin receptors in trigeminal ganglion neurons to hyperalgesia via satellite glial interleukin-1beta paracrine mechanism. Brain Behav. Immun. 22, 1016–1023 (2008).

    CAS  PubMed  Google Scholar 

  117. 117.

    Romero-Reyes, M., Pardi, V. & Akerman, S. A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to nociceptive trigeminal activation: Role of CGRP in orofacial pain. Exp. Neurol. 271, 95–103 (2015).

    CAS  PubMed  Google Scholar 

  118. 118.

    Burstein, R., Yamamura, H., Malick, A. & Strassman, A. M. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J. Neurophysiol. 79, 964–982 (1998).

    CAS  PubMed  Google Scholar 

  119. 119.

    Strassman, A. M., Raymond, S. A. & Burstein, R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384, 560–564 (1996).

    CAS  PubMed  Google Scholar 

  120. 120.

    Lukács, M. et al. Dural administration of inflammatory soup or Complete Freund’s Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion. J. Headache Pain 16, 564 (2015).

    PubMed  Google Scholar 

  121. 121.

    Lukacs, M. et al. KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1beta in the rat trigeminal ganglion. J. Headache Pain 17, 64 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Lukacs, M. et al. Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72). J. Headache Pain 18, 39 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Reuter, U. A review of monoclonal antibody therapies and other preventative treatments in migraine. Headache 58 (Suppl. 1), 48–59 (2018).

    PubMed  Google Scholar 

  124. 124.

    Edvinsson, L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 57 (Suppl. 2), 47–55 (2017).

    PubMed  Google Scholar 

  125. 125.

    Kurth, T. et al. Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study. BMJ 342, c7357 (2011).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Lyman, M., Lloyd, D. G., Ji, X., Vizcaychipi, M. P. & Ma, D. Neuroinflammation: the role and consequences. Neurosci. Res. 79, 1–12 (2014).

    CAS  PubMed  Google Scholar 

  127. 127.

    DiSabato, D. J., Quan, N. & Godbout, J. P. Neuroinflammation: the devil is in the details. J. Neurochem. 139 (Suppl. 2), 136–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Barnes, P. J. Neurogenic inflammation in airways. Int. Arch. Allergy Appl. Immunol. 94, 303–309 (1991).

    CAS  PubMed  Google Scholar 

  129. 129.

    Black, P. H. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav. Immun. 16, 622–653 (2002).

    CAS  PubMed  Google Scholar 

  130. 130.

    Brack, A., Rittner, H. L. & Stein, C. Neurogenic painful inflammation. Curr. Opin. Anaesthesiol. 17, 461–464 (2004).

    PubMed  Google Scholar 

  131. 131.

    Waeber, C. & Moskowitz, M. A. Migraine as an inflammatory disorder. Neurology 64, S9–S15 (2005).

    PubMed  Google Scholar 

  132. 132.

    Levy, D. Migraine pain, meningeal inflammation, and mast cells. Curr. Pain Headache Rep. 13, 237–240 (2009).

    PubMed  Google Scholar 

  133. 133.

    Shepherd, S. L., Williamson, D. J., Beer, M. S., Hill, R. G. & Hargreaves, R. J. Differential effects of 5-HT1B/1D receptor agonists on neurogenic dural plasma extravasation and vasodilation in anaesthetized rats. Neuropharmacology 36, 525–533 (1997).

    CAS  PubMed  Google Scholar 

  134. 134.

    Buzzi, M. G. & Moskowitz, M. A. The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br. J. Pharmacol. 99, 202–206 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Lars Edvinsson.

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Edvinsson, L., Haanes, K.A. & Warfvinge, K. Does inflammation have a role in migraine?. Nat Rev Neurol 15, 483–490 (2019).

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