Review Article

Signal Transduction Pathways in Pathogenesis of Migraine

Qingling Zhai^1,2, Xiaowen Song², Danna Xie^1,2 and Jinbo Chen²*

¹Binzhou Medical University, Yantai City, China

²Department of Neurology, The Affiliated Hospital of Binzhou Medical University, China

Submission: September 21, 2021; Published: October 18, 2021

*Corresponding author: Jinbo Chen, Department of Neurology, The Affiliated Hospital of Binzhou Medical University, Binzhou City, China

How to cite this article: Qingling Zhai, Xiaowen Song, Danna Xie and Jinbo Chen*. Signal Transduction Pathways in Pathogenesis of Migraine. Open Access J Neurol Neurosurg 2021; 16(2): 555932. DOI: 10.19080/OAJNN.2021.16.555932.

Abstract

Migraine is one of the most common neurological diseases. However, the pathogenesis of migraine is not completely clear, and there is no specific cure. Most researches showed that the pathophysiology of migraine is related to abnormal pain regulation, central sensitization, increased cortical excitability and neurogenic inflammation. Although studies have found that the key signaling pathways in migraine are dysregulated, the research on signal transduction pathways is incomplete. The goal of this review will be to the signal transduction pathways may involve in the pathogenesis of migraine, and focused on the central sensitization, the sensitization of trigeminal vascular system and the role of microglia in migraine. In the end we proposed research direction of target-based drugs under migraine signaling transduction pathway. Migraine is a common multiple disease, accurate diagnosis and etiology research play an important role in the treatment of migraine. We review the signaling pathways involved in the pathogenesis of migraine. Further studies based on signal transduction pathways will help to have a deeper understanding of the pathogenesis of migraine to help aid better treatment to patients with migraine.

Keywords: Migraine; Signal transduction pathways; Trigeminal vascular system; Microglia

Introduction

Migraine, a common primary headache disorder, is currently ranked as the third most prevalent medical condition and the second most disabling neurological disorder in the world [1]. Unfortunately, the recent therapeutic options on the market have not progressed accordingly. In fact, 50% of patients reported they are dissatisfied with the pain recurrence and 80% of patients discontinue therapy due to supplementary dosing [2]. Migraine was primarily proposed to be a vascular disease caused by the abnormal vasodilation which is controlled by the trigeminal nerve [3,4]. Hence, triptans as a vasoconstrictive drug which mostly bind to 5-hydroxytryptamine receptor 1B (5-HT1B) and 5-hydroxytryptamine receptor 1D (5-HT1D) receptors within cerebral blood vessels appear. However, a lot of recent experimental evidences challenge this hypothesis [5,6]. Cerebral blood vessels vasodilation is not the primary cause but only an epiphenomenon in migraine pathophysiology [7-9]. In fact, migraine is a pathophysiologically complex disease. Although findings emphasise that vasodilation is not the cause of migraine, vascular mechanisms might nonetheless have an important role effect in the pathophysiology of migraine [5]. The pathophysiology of migraine now supposed to be a dysfunctional sensory modulatory network involves the activation and sensitization of the trigeminocervical complex nociceptors, Cortical Spreading Depression (CSD) as well as abnormal brainstem activity [10-12]. Sensory transmission of nociceptive signals from peripheral trigeminal nerve sensations, such as intracranial and extracranial structures for pain sensing, including the dura mater and peripheral blood vessels of the trigeminal nerve transmit to second order neurons. From here, the ascending projection of the secondary neurons of TNC terminates in brainstem, hypothalamic, and thalamic nuclei [13]. In the cascade of events regarding vascular function, second order neurons also involved in the release of several neurotransmitters [14]. For example, calcitonin gene-related peptide (CGRP), which is a well-known vasodilatator, leading to subsequent increase in vessel diameter and blood flow in the meninges and cortex, both of which could further activate vascular and meningeal nociceptors leading to migraine headache [13].

Signaling pathways in migraine

Many of molecular signaling pathways that neuron homeostasis is highly regulated are abnormally activated or repressed in human migraine and in experimental models of migraine. Such abnormalities are not prone the self-renewal, proliferative, survival, and differentiation. In general, these pathways are intricate, with extrinsic and intrinsic molecular signals and regulatory elements. Many of these “pathways” are not linear, but rather interwoven networks of signaling mediators that feed into one another, facilitating intrapathway cross talk. Thus, this review will highlight signaling pathways cascades in migraine pathology and introduce the activation of microglial intracellular cascades work to these pathways.

MAPK Pathway

Mitogen-activated protein kinases (MAPKs), which consists of c-Jun N-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK), representing extracellular stimuli into intracellular posttranslation and transcription by phosphorylation [15-17]. MAPK signaling pathways can be triggered by several different stimulus, not only proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β), substance P but also inflammatory proteins, such as Inducible Nitric Oxide (iNOS), cyclooxygenase-2 (COX-2), ionized calcium binding adapter 1 (IBA-1) as well as pathological conditions, including oxidative, genotoxic, and osmotic stress [18-21]. While the phosphorylation of MAPK also contributes to the transcription factors which may increase and sensitize proinflammatory cytokines and other pain mediators, leading to induce and maintain even exacerbate of neuropathic pain status [18,22-24]. The MAPK activates several downstream signaling pathways through nontranscriptional processing and increasing gene transcription to produce short-term functional changes and long-term adaptive changes [25]. For example, phosphorylated ERK translocates to the nucleus activates nuclear factor erythroid 2-related factor 2 (Nrf2), which is a protein can regulates the heme oxygenase-1 (HO-1) expression to against oxidation and inflammation [26-28]. In addition, previous studies have reported that activated ERK may induce the activation of ribosomal s6 kinase (Rsk2), which then phosphorylates the transcription factor cAMP response element-binding protein (CREB) on serine 133 [29], binding to the DNA promoter regions and initiating the genes transcription [30-33]. The role of MAPK signaling in migraine has been demonstrated in animal models of nitroglycerin (NTG) [34,35]. Both Sun et al. [28]and Lai et al. [36] have explored the anti-migraine function of rhynchophylline. They all reported that the protection effect of rhynchophylline revised the activity of MAPK/ Nuclear factor-KB (NF-κB) pathway by NTG. In the migraine model of electrical stimulation of the superior sagittal sinus, chronic administration of paroxetine suppresses activation of p38 MAPK in the TNC compared with in the model group [37]. In addition, p- ERK appears to be a better marker in the dura mater, trigeminal ganglion (TG), and TNC for central sensitization induced by NTG infusion [38]. On the one hand p- ERK increase recepter plasticity, such as α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl- D-aspartate (NMDA) receptors, on the other hand it can suppress the activity of potassium Kv4.2 channels, induce and maintain central sensitization [39]. Based on these studies, there is a close relationship between MAPK phosphorylation and NTG in contributing to the development and maintenance of migraine.

cAMP/PKA/CREB pathway

As one of the earliest identified and ubiquitous secondary messengers, cyclic adenosine 3’,5’-monophosphate (cAMP), is generated from adenosine Triphosphate (ATP) via adenylyl cyclases (ACs) and degraded via phosphodiesterases (PDEs), which catabolizes 1cAMP into 5AMP [40,41]. The widely known downstream effector of cAMP signaling is protein kinase A (PKA). PKA is made of two regulatory subunits (PKA-R) and two catalytic subunits (PKA-C). It was reported that cAMP-PKA signaling cascades is closely related to an array of transcriptional cascades involved in immune response, cellular metabolism promotes the synthesis of presynaptic neurotransmitters and synaptic plasticity, which is a prime mechanism underlying chronic pain, such as migraine [42,43]. Previous studies have demonstrated the involvement of cAMP-PKA pathway in inflammatory pain [44], neuropathic pain [45]and bone cancer pain [46]. Activated PKA phosphorylates and catalyzes phosphorylation of regulatory proteins causing a series of downstream changes. Not only including CREB phosphorylation, a key transcriptional co-factor that initiates biological processes, but also the activity of ion channels, cellular motor proteins and many enzymes involved in intermediate metabolism [47,48]. These phosphorylation events intertwine cAMP-PKA signaling with other cellular messengers and signaling cascades, providing multiple feedback loops and further modulating cAMP signaling, which indicates the crucial role of the cAMP-PKA pathway in the induction and maintenance of synapse plasticity in the nervous system [49,50].

Previous studies have revealed that the cAMP-PKA-CREB signaling is involved in migraine associated behaviors in animals. Consistently, migraineurs have an increased in plasma cAMP and CGRP levels during migraine attacks [51]. Moreover, elevated levels of cyclic AMP can active trigeminal neurons, leading to central sensitization [52]. Furthermore, previous study showed cilostazol, a selective inhibitor of phosphodiesterase 3(PDE3), increased intracellular levels of cyclic AMP inducing more migraine-like attacks [53]. The behavioral test of mechanical allodynia recovered with the inhibition of cAMP-PKA-CREB signaling by PKA inhibitor, suggesting that the effects of PKA inhibitor may be through regulation of the signaling pathway [54,55]. Interestingly, previous studies showed that both PKA inhibitors, H-89 and PKI (14-22) can block the regulation of CGRP release and regulate pain sensitization [56]. In all, these data suggests that the cAMP pathway offers an interesting exploration for initiating head pain and migraine, which deserves future focus.

NF-κB pathway

NF-κB is a pleiotropic transcriptional factor which plays a pivotal role in transcription of the genes encoding the neuroinflammation, immune responses, cell cycle and survival as well as nociception [56]. In an inactive state NF-кB is sequestered within the cytoplasm by binding with IκBα (IκB family of inhibitory proteins). Once IκBα is phosphorylated and degradation, p-IκBα releasing NF-κB to enter the nucleus, resulting in initiating gene expression [57-59]. Under basal conditions, NF-κB is located within the cytoplasm, but following specific stimuli, its p65 subunit translocates into the nucleus, causing the initiation of transcriptional activity [60]. Various studies have showed that NF-κB and its downstream proinflammatory cytokines contribute to migraine. For example, studies have showed that parthenolide attenuated migraine via suppression of the NF-kB pathway after GTN triggered transcriptional events [61]. NF-kB, which controls iNOS expression following proinflammatory cytokine administration, was crucial to the transcription of iNOS following GTN infusion in rat meninges [57]. Besides, pretreatment of valproate (VPA), against migraine with mild side effects, could inhibit the activation of NF-кB [62]. The pathways involved in the induction of migraine by NTG actually initiates the activation of NF-kB [63]. To accomplish this, nitric oxide (NO) enhances IκBα degradate from the IκBα–NF-κB complex, then regulating the expression of inflammatory mediators, such as TNF-α, IL-1β and COX-2[64].

NO/ sGC/ cGMP pathway

During the past three decades multiple lines of evidence shows that NO is implicated in the migraine pathogenesis [65,66]. Once formed, NO binds with its high-affinity receptor, soluble guanylyl cyclase (sGC) resulting in enzyme activation [67]. The activated sGC converts guanosine triphosphate (GTP) into the second messenger guanosine3’, 5’-cyclic monophosphate (cGMP). In addition, cGMP phosphorylates protein kinase G (PKG) [68], which phosphorylates ion channels eliciting decreased intracellular calcium. Upregulation of the NO/sGC/cGMP pathway has been implicated in migraine [69,70]. To support the role of the NO-sGC pathway in migraine, Manel Ben Aissa probed that the novel sGC stimulator, VL-102, stimulates cGMP production and induces migraine-associated hyperalgesia [71]. Furthermore, ODQ, sGC inhibitor effectively blocked chronic migraineassociated pain, which is produced by NTG experimental models of migraine [72]. Simplistically, cGMP is degradated to GMP by hosphodiesterase 5 (PDE5), acting as a negative regulator of this pathway. A PDE5 inhibitor sildenafil was found to evoke migrainelike pain in both migraineurs [73] and mice [74]. Taken together, these results strengthen the notion of increased NO as a hallmark of migraine-associated symptoms and establishes NTG as a useful translationally significant model of migraine.

Interaction between signaling pathways

As mentioned previously, these complex signal transduction pathways are not linear and, in some cases, cross-talk between and among various pathways occurs in the migraine. Some examples of convergence between pathways were discussed earlier. For example, in Lai et al. [36] studies, the function of rhynchophylline on migraine was exerted by inhibiting MAPK/ NF-кB pathway. The results show that cooperation between the MAPK and NF-kB signaling pathways contribute to understanding the pathogenesis of migraine and mechanisms by which NTG contributes to migraine [66,75]. Furthermore, the converge of cAMP and cGMP pathways, leading to initiation of the same migraine attacks, which is demonstrated in attacks induced by CGRP and sildenafil [76]. In other cases, show that female ovariectomized rats significantly reduce the expression of brain derived neurotrophic factor (BDNF), TrkB, p-CREB and p-ERK in NTG-induced migraine model [77]. In contrast, giving estrogen is also able to reverse the suppression in BDNF, TrkB, p-CREB and p-ERK These data suggest that BDNF/TrkB and ERK/CREB axes are important for the induction or development of estrogen signals in the migraine [78].

Neuron–Glia Signaling in Trigeminal Ganglion

Increasing evidence suggests that neuronal–glia cell interactions are likely to play an important role in migraine pathophysiology, such as central sensitization and peripheral sensitization [79,80]. Activated microglia can communicate with neurons through chemotaxis and produce various proinflammatory cytokines leading to amplify nociceptive signals. Previous studies demonstrated that microglia- derived IL-18 is involved in migraine signaling pathway [82,83]. In inflammatory soup (IS) dural infusions mouse models of migraine, activated microglia synthesize and release IL-18, then, promoting NF-kB phosphorylation [84]. And resulting in gene expression, such as BDNF, which is a key molecule for maintaining migraine hypersensitivity. Furthermore, suppression of IL-18 attenuated nociceptive behavior and significantly inhibited the activation of NF-kB phosphorylation [85]. LPS-activated microglia increase the level of TNF-α, which is involved in various diseases, such as migraine [86]. Inflammatory mediators like TNF-α, acts on TLR4, and involves MAPK family member (P38, ERK, and JNK) signaling, resulting in NF-kB-mediated transcription [87,88]. Lalita Subedi [89] confirmed that regulation of JNK/NF-kB/TNF-αsignaling contribute to migraine. Therefore, neuron–glia interactions have been shown in stages of the TNF-αthey secrete, mediating the regulation of NF-κB and JNK signaling cascades. In Long at al. [39] study, enhancement of P2X4R expression in the TNC was found in chronic migraine mice. Extensive evidences have shown that P2X4Rs are mainly expressed in microglia, contributing to inflammatory pain, neuropathic pain, and migraine [90-93]. Activated P2X4Rs evoke p38-MAPK phosphorylation, resulting in MAPK signaling downstream [94]. Furthermore, 5-BDBD, The P2X4R inhibitor, prevents mechanical hyperalgesia [95]. Hence, it is inferred that a certain microglia-regulated P2X4R expression may be regulating migraine occurrence. On the other hand, Cortical spreading depression (CSD) is a phenomenon that results in prolonged suppression of electrical activity [96]. This slowly propagating wave seems to be involved in stroke, head trauma, migraine and epilepsy [97,98]. Neuron-glial interactions is thought to play a role in CSD occurrence. Microglia express voltage-sensitive ion channels, including Nav1.1, Kv1.3, and Kv1.5, and are thought to sense electrical activity pertaining to CSD [99- 101].

Conclusion

Migraine is a common multiple disease, accurate diagnosis and etiology research play an important role in the treatment of migraine. Although no animal model of migraine is sufficient to explain how pain develops, what these hypothesized models have in common is the dysregulation of key signaling pathways. We review the signaling pathways involved in the pathogenesis of migraine, including migraine-related pathological processes, such as inflammatory response, synaptic remodeling, and central sensitization. At present, there are still a lot of deficiencies in the pathogenesis of migraine. Further research based on signal transduction pathways will help to have a deeper understanding of the occurrence, development and pathogenesis of migraine.

Authors’ contribution

All authors read and approved the final manuscript. Qingling Zhai and Xiaowen Song edited the manuscript. Danna Xie collected the literatures. Jinbo Chen designed and monitored this manuscript. Qingling Zhai and Xiaowen Song contributed equally to this paper.

Funding source

This work was supported by the following grants: Natural Science Foundation of Shandong Province (ZR2017LH032), Projects of Medical and Health Technology Development Program of Shandong Province (2019WS322).

References

1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. LANCET 388(10053) :1545-1602.
2. Sicuteri F (1972) Headache as possible expression of deficiency of brain 5-hydroxytryptamine (central denervation supersensitivity). Headache 12(2): 69-72.
3. Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J (1985) Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 62(1): 131-136.
4. Houston DS, Vanhoutte PM (1986) Serotonin and the vascular system. Role in health and disease, and implications for therapy. Drugs 31(2): 149-163.
5. Amin FM, Asghar MS, Hougaard A, et al. (2013) Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 12(5) :454-446.
6. Charles A (2013) Vasodilation out of the picture as a cause of migraine headache. Lancet Neurol 12(5): 419-420.
7. Humphrey PP, Feniuk W, Perren MJ, I J Beresford, M Skingle, et al. (1990) Serotonin and migraine. Ann N Y Acad Sci 600: 587-598.
8. Pietrobon D, Moskowitz MA (2013) Pathophysiology of migraine. Annu Rev Physiol 75: 365-391.
9. Akerman S, Holland PR, Goadsby PJ Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12(10): 570-584.
10. Schulte LH, May A (2016) The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139: 1987-1993.
11. May A, Schulte LH (2016) Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 12(8): 455-464.
12. Charles A (2009) Advances in the basic and clinical science of migraine. Ann Neurol 65(5): 491-498.
13. Deen M, Correnti E, Kamm K, Tim K, Laura P, et al. (2017) Blocking CGRP in migraine patients - a review of pros and cons. J Headache Pain 18(1): 96.
14. Goadsby PJ, Lipton RB, Ferrari MD (2002) Migraine--current understanding and treatment. N Engl J Med 346(4): 257-270.
15. Kuzmich NN, Sivak KV, Chubarev VN, Yuri B Porozov, Tatiana N Savateeva-L, et al. (2017) TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis. Vaccines (Basel) 5(4): 34.
16. Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9(9): 726-735.
17. Widmann C, Gibson S, Jarpe MB, Johnson GL (1999) Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79(1): 143-180.
18. Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1): 23-36.
19. Svensson CI, Marsala M, Westerlund A, Nigel A Calcutt, Wendy M Campana, et al. (2003) Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86(6):1534-1544.
20. Sun X, Zeng H, Wang Q, Qingwen Y, Jianxiong Wu, et al. (2018) Glycyrrhizin ameliorates inflammatory pain by inhibiting microglial activation-mediated inflammatory response via blockage of the HMGB1-TLR4-NF-kB pathway. EXP CELL RES 369(1):112-119.
21. Zhu MD, Zhao LX, Wang XT, Gao YJ, Zhang ZJ (2014) Ligustilide inhibits microglia-mediated proinflammatory cytokines production and inflammatory pain. Brain Res Bull 109:54-60.
22. Obata K, Yamanaka H, Kobayashi K, Yi Dai, Toshiyuki Mizushima, et al. (2004) Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci 24(45): 10211-10222.
23. Xu JT, Xin WJ, Wei XH, Yu-Xing Ge, et al. (2007) p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury. Exp Neurol 204(1): 355-365.
24. Xu L, Huang Y, Yu X, Nan Yang, Pingping Zuo, et al. (2007) The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury. Anesth Analg 105(6):1838-1844.
25. Obata K, Noguchi K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 74(21): 2643-2653.
26. Li C, Yang F, Liu F, Li D, Yang T (2018) NRF2/HO-1 activation via ERK pathway involved in the anti-neuroinflammatory effect of Astragaloside IV in LPS induced microglial cells. Neurosci Lett 666:104-110.
27. Li C, Chen T, Zhou H, Chao Zhang, Yu Feng, et al. (2018) Schisantherin A Attenuates Neuroinflammation in Activated Microglia: Role of Nrf2 Activation Through ERK Phosphorylation. Cell Physiol Biochem 47(5):1769-1784.
28. Sun GY, Chen Z, Jasmer KJ, Dennis Y Chuang, Zezong Gu, et al. (2015) Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1. Plos One 10(10): e141509.
29. Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273(5277): 959-963.
30. Impey S, Obrietan K, Wong ST, S Poser, S Yano, et al. (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21(4): 869-883.
31. Obrietan K, Impey S, Smith D, Athos J, Storm DR (1999) Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274(25):17748-17756.
32. English JD, Sweatt JD (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272(31):19103-19106.
33. Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD (1998) The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1(7): 602-609.
34. Hansen RR, Nielsen CK, Nasser A, Stine I M Thomsen, Laura F Eghorn, et al. (2011) P2X7 receptor-deficient mice are susceptible to bone cancer pain. Pain 152(8): 1766-1776.
35. Munoz FM, Gao R, Tian Y, Brian A H, James E B, et al. (2017) Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice. Sci Rep 7(1): 3539.
36. Lai T, Chen L, Chen X, Jianquan H, Peiyu L, et al. (2019) Rhynchophylline attenuates migraine in trigeminal nucleus caudalis in nitroglycerin-induced rat model by inhibiting MAPK/NF-кB signaling. Mol Cell Biochem 461(1-2): 205-212.
37. Wang C, Bi W, Liang Y, Xiuna Jing, Songhua Xiao, et al. (2012) Paroxetine engenders analgesic effects through inhibition of p38 phosphorylation in a rat migraine model. Neural Regen Res 7(13):1006-1012.
38. Ji RR, Woolf CJ (2001) Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 8(1):1-10.
39. Long T, He W, Pan Q, Shanshan Zhang, Dunke Zhang, et al. (2020) Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model. J Headache Pain21: 4.
40. Beavo JA, Brunton LL (2002) Cyclic nucleotide research -- still expanding after half a century. Nat Rev Mol Cell Biol 3(9): 710-718.
41. Conti M, Jin SL (1999) The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 63: 1-38.
42. Waltereit R, Weller M (2003) Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27: 99-106.
43. Luo C, Kuner T, Kuner R (2014) Synaptic plasticity in pathological pain. Trends Neurosci 37(6): 343-355.
44. Hingtgen CM, Waite KJ, Vasko MR (1995) Prostaglandins facilitate peptide release from rat sensory neurons by activating the adenosine 3',5'-cyclic monophosphate transduction cascade. J Neurosci 15: 5411-5419.
45. Zheng JH, Walters ET, Song XJ (2007) Dissociation of dorsal root ganglion neurons induces hyperexcitability that is maintained by increased responsiveness to cAMP and cGMP. J Neurophysiol 97(1):15-25.
46. Zhu G, Dong Y, He X, Ping Zhao, Aixing Yang, et al. (2016) Radiotherapy Suppresses Bone Cancer Pain through Inhibiting Activation of cAMP Signaling in Rat Dorsal Root Ganglion and Spinal Cord. Mediators Inflamm 2016: 5093095.
47. Anderson MP, Berger HA, Rich DP, Gregory RJ, Smith AE, et al. (1991) Nucleoside triphosphates are required to open the CFTR chloride channel. Cell 67(4): 775-784.
48. Catterall WA (2015) Regulation of Cardiac Calcium Channels in the Fight-or-Flight Response. Curr Mol Pharmacol 8: 12-21.
49. Bjorgo E, Solheim SA, Abrahamsen H, George S Baillie, Kim M Brown, et al. (2010) Cross talk between phosphatidylinositol 3-kinase and cyclic AMP (cAMP)-protein kinase a signaling pathways at the level of a protein kinase B/beta-arrestin/cAMP phosphodiesterase 4 complex. Mol Cell Biol 30(7): 1660-1672.
50. Ahuja M, Jha A, Maleth J, Park S, Muallem S (2014) cAMP and Ca(2)(+) signaling in secretory epithelia: crosstalk and synergism. Cell Calcium 55(6): 385-393.
51. Kruuse C, Frandsen E, Schifter S, Thomsen LL, Birk S, et al. (2004) Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache. Cephalalgia 24(7): 547-553.
52. Ingram SL, Williams JT (1996) Modulation of the hyperpolarization-activated current (Ih) by cyclic nucleotides in guinea-pig primary afferent neurons. J Physiol 492 (Pt 1): 97-106.
53. Guo S, Olesen J, Ashina M (2014) Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137(Pt 11): 2951-2959.
54. Chen T, Koga K, Descalzi G (2014) Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury. Mol Pain 10: 33.
55. Fu Y, Han J, Ishola T, Michelle Scerbo, Hita Adwanikar, et al. (2008) PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior. Mol Pain 4: 26.
56. Yue X, Tumati S, Navratilova E, Dagmar Strop, Paul A St John, et al. (2008) Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner. Eur J Pharmacol 584(2-3): 272-277.
57. Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269(7): 4705-4708.
58. Brown K, Park S, Kanno T, Franzoso G, Siebenlist U (1993) Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci USA 90(6): 2532-2536.
59. Ghosh S, Baltimore D (1990) Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B Nature 344: 678-682.
60. Greco R, Tassorelli C, Cappelletti D, Sandrini G, Nappi G (2005) Activation of the transcription factor NF-kappa B in the nucleus trigeminalis caudalis in an animal model of migraine. Neurotoxicology 26(5): 795-800.
61. Magni P, Ruscica M, Dozio E, Giorgio Sandrini, Giuseppe Nappi, et al. (2012) Parthenolide Inhibits the LPS-induced Secretion of IL-6 and TNF-α and NF-κB Nuclear Translocation in BV-2 Microglia. Phytother Res 26(5): 1405-1409.
62. Li Y, Zhang Q, Qi D, Li Zhang, Lian Yi, et al. (2016) Valproate ameliorates nitroglycerin-induced migraine in trigeminal nucleus caudalis in rats through inhibition of NF-к J Headache Pain 17: 1-9.
63. Tassorelli C, Greco R, Morazzoni P, Sandrini G, Nappi G et al. (2005) Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine. Cephalalgia 25(8): 612-621.
64. Luo JG, Zhao XL, Xu WC, Xue-Jun Zhao, Jun-Nan Wang, et al. (2014) Activation of spinal NF-kappaB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis. Arthritis Rheumatol 66(4): 896-906.
65. Olesen J (2010) Nitric oxide-related drug targets in headache. Neurotherapeutics 7(2):183-190.
66. Olesen J (2008) The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther 120(2): 157-171.
67. Ben AM, Tipton AF, Bertels Z, Ronak Gandhi, Laura S Moye, et al. (2018) Soluble guanylyl cyclase is a critical regulator of migraine-associated pain. Cephalalgia 38(8): 1471-1484.
68. Moncada S, Higgs EA (2006) The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 147 (Suppl 1): S193-S201.
69. Taffi R, Vignini A, Lanciotti C, Luconi R, Nanetti L, et al. (2005) Platelet membrane fluidity and peroxynitrite levels in migraine patients during headache-free periods. Cephalalgia 25(5): 353-358.
70. Iversen HK, Olesen J, Tfelt-Hansen P (1989) Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 38(1): 17-24.
71. Ben AM, Lee SH, Bennett BM, Thatcher GR (2016) Targeting NO/cGMP Signaling in the CNS for Neurodegeneration and Alzheimer's Disease. Curr Med Chem 23(24): 2770-2788.
72. Pradhan AA, Bertels Z, Akerman S (2018) Targeted Nitric Oxide Synthase Inhibitors for Migraine. Neurotherapeutics 15(2): 391-401.
73. Kruuse C, Thomsen LL, Birk S, Olesen J (2003) Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126(Pt 1): 241-247.
74. Pradhan AA, Smith ML, Mc Guire B, Igal Tarash, Christopher J Evans, et al. (2014) Characterization of a novel model of chronic migraine. Pain 155(2): 269-274.
75. Reuter U, Bolay H, Jansen-Olesen I, A Chiarugi, M Sanchez del Rio, et al. (2001) Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124(Pt 12): 2490-2502.
76. Younis S, Christensen CE, Toft NM, Thomas Søborg, Faisal M Amin, et al. (2019) Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil. Cephalalgia 39(14): 1776-1788.
77. Gupta S, McCarson KE, Welch KM, Berman NE (2011) Mechanisms of pain modulation by sex hormones in migraine. Headache 51(6): 905-922.
78. Guo JQ, Deng HH, Bo X, Yang XS (2017) Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine. Biol Open 6: 8-16.
79. Martins LB, Teixeira AL, Domingues RB (2017) Neurotrophins and Migraine. Vitam Horm104: 459-473.
80. Dodick D, Silberstein S (2006) Central sensitization theory of migraine: clinical implications. Headache 46 (Suppl 4) : S182-S191.
81. Tozaki-Saitoh H, Tsuda M, Miyata H, Kazuaki Ueda, Shinichi Kohsaka, et al. (2008) P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 28(19): 4949-4956.
82. Khaiboullina SF, Mendelevich EG, Shigapova LH, Elena Shagimardanova, Guzel Gazizova, et al. (2017) Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family. Front Cell Neurosci 11: 263.
83. Shi S, Han Y, Wang D, Ping Guo, Jiali Wang, et al. (2020) PD-L1 and PD-1 expressed in trigeminal ganglia may inhibit pain in an acute migraine model. Cephalalgia 40(3): 288-298.
84. Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K (2008) Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 28(48): 12775-12787.
85. Gong Q, Lin Y, Lu Z, Xiao Z (2020) Microglia-Astrocyte Cross Talk through IL-18/IL-18R Signaling Modulates Migraine-like Behavior in Experimental Models of Migraine. Neuroscience 451: 207-215.
86. Ramachandran R (2018) Neurogenic inflammation and its role in migraine. Semin Immunopathol 40: 301-314.
87. Ock J, Han HS, Hong SH, et al. (2010) Obovatol attenuates microglia-mediated neuroinflammation by modulating redox regulation. Br J Pharmacol 159(8): 1646-1662.
88. Zhang F, Jiang L (2015) Neuroinflammation in Alzheimer's disease. Neuropsychiatr Dis Treat 11: 243-256.
89. Subedi L, Venkatesan R, Kim SY (2017) Neuroprotective and Anti-Inflammatory Activities of Allyl Isothiocyanate through Attenuation of JNK/NF-kappaB/TNF-alpha Signaling. Int J Mol Sci 18(7): 1423.
90. Liu C, Zhang Y, Liu Q, Li Jiang, Maolin Li, et al. (2018) P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia. Mol Pain14: 2070367590.
91. Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al. (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424: 778-783.
92. Trang T, Beggs S, Salter MW (2012) ATP receptors gate microglia signaling in neuropathic pain. Exp Neurol 234(2): 354-361.
93. Chessell IP, Hatcher JP, Bountra C, Anton D Michel, Jane P Hughes, et al. (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114(3): 386-396.
94. Ulmann L, Hirbec H, Rassendren F (2010) P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO J 29(4): 2290-2300.
95. Tsuda M, Masuda T, Tozaki-Saitoh H, Inoue K (2013) P2X4 receptors and neuropathic pain. Front Cell Neurosci 7:191.
96. Leao AA (1947) Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol 10(6): 409-414.
97. Read SJ, Parsons AA (2000) Sumatriptan modifies cortical free radical release during cortical spreading depression. A novel antimigraine action for sumatriptan? Brain Res 870(1-2): 44-53.
98. Guedes RC, Cavalheiro EA (1997) Blockade of spreading depression in chronic epileptic rats: reversion by diazepam. Epilepsy Res 27(1): 33-40.
99. Schilling T, Eder C (2007) Ion channel expression in resting and activated microglia of hippocampal slices from juvenile mice. Brain Res 1186: 21-28.
100. Schilling T, Quandt FN, Cherny VV, W Zhou, U Heinemann, et al. (2000) Upregulation of Kv1.3 K(+) channels in microglia deactivated by TGF-beta. Am J Physiol Cell Physiol 279(4): C1123-C1134.
101. Black JA, Liu S, Waxman SG (2009) Sodium channel activity modulates multiple functions in microglia. GLIA 57(10):1072-1081.