Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
The Journal of Headache and Pain
Published in: The Journal of Headache and Pain 1/2022

Open Access 01-12-2022 | Migraine | Research

Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine

Authors: Wei Zhang, Ming Lei, Qianwen Wen, Dunke Zhang, Guangcheng Qin, Jiying Zhou, Lixue Chen

Published in: The Journal of Headache and Pain | Issue 1/2022

Login to get access

Abstract

Background

The pathogenesis of chronic migraine remains unresolved. Recent studies have affirmed the contribution of GLUA1-containing AMPA receptors to chronic migraine. The dopamine D2 receptor, a member of G protein-coupled receptor superfamily, has been proven to have an analgesic effect on pathological headaches. The present work investigated the exact role of the dopamine D2 receptor in chronic migraine and its effect on GLUA1-containing AMPA receptor trafficking.

Methods

A chronic migraine model was established by repeated inflammatory soup stimulation. Mechanical, periorbital, and thermal pain thresholds were assessed by the application of von Frey filaments and radiant heat. The mRNA and protein expression levels of the dopamine D2 receptor were analyzed by qRT‒PCR and western blotting. Colocalization of the dopamine D2 receptor and the GLUA1-containing AMPAR was observed by immunofluorescence. A dopamine D2 receptor agonist (quinpirole) and antagonist (sulpiride), a PI3K inhibitor (LY294002), a PI3K pathway agonist (740YP), and a GLUA1-containing AMPAR antagonist (NASPM) were administered to confirm the effects of the dopamine D2 receptor, the PI3K pathway and GULA1 on central sensitization and the GLUA1-containing AMPAR trafficking. Transmission electron microscopy and Golgi-Cox staining were applied to assess the impact of the dopamine D2 receptor and PI3K pathway on synaptic morphology. Fluo-4-AM was used to clarify the role of the dopamine D2 receptor and PI3K signaling on neuronal calcium influx. The Src family kinase (SFK) inhibitor PP2 was used to explore the effect of Src kinase on GLUA1-containing AMPAR trafficking and the PI3K signaling pathway.

Results

Inflammatory soup stimulation significantly reduced pain thresholds in rats, accompanied by an increase in PI3K-P110β subunit expression, loss of dopamine receptor D2 expression, and enhanced GLUA1-containing AMPA receptor trafficking in the trigeminal nucleus caudalis (TNC). The dopamine D2 receptor colocalized with the GLUA1-containing AMPA receptor in the TNC; quinpirole, LY294002, and NASPM alleviated pain hypersensitivity and reduced GLUA1-containing AMPA receptor trafficking in chronic migraine rats. Sulpiride aggravated pain hypersensitivity and enhanced GLUA1 trafficking in CM rats. Importantly, the anti-injury and central sensitization-mitigating effects of quinpirole were reversed by 740YP. Both quinpirole and LY294002 inhibited calcium influx to neurons and modulated the synaptic morphology in the TNC. Additional results suggested that DRD2 may regulate PI3K signaling through Src family kinases.

Conclusion

Modulation of GLUA1-containing AMPA receptor trafficking and central sensitization by the dopamine D2 receptor via the PI3K signaling pathway may contribute to the pathogenesis of chronic migraine in rats, and the dopamine D2 receptor could be a valuable candidate for chronic migraine treatment.
Appendix
Available only for authorised users
Literature
1.
Aurora SK, Brin MF (2017) Chronic Migraine: An Update on Physiology, Imaging, and the Mechanism of Action of Two Available Pharmacologic Therapies. Headache 57(1):109–125PubMedCrossRef
2.
3.
Boyer N, Dallel R, Artola A, Monconduit L (2014) General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. Pain 155(7):1196–1205PubMedCrossRef
4.
Harriott AM, Strother LC, Vila-Pueyo M, Holland PR (2019) Animal models of migraine and experimental techniques used to examine trigeminal sensory processing. J Headache Pain 20(1):91PubMedPubMedCentralCrossRef
5.
Torres-Ferrús M, Ursitti F, Alpuente A et al (2020) From transformation to chronification of migraine: pathophysiological and clinical aspects. J Headache Pain 21(1):42PubMedPubMedCentralCrossRef
6.
Vikelis M, Mitsikostas DD (2007) The role of glutamate and its receptors in migraine. CNS Neurol Disord Drug Targets 6(4):251–257PubMedCrossRef
7.
Kopach O, Krotov V, Belan P, Voitenko N (2015) Inflammatory-induced changes in synaptic drive and postsynaptic AMPARs in lamina II dorsal horn neurons are cell-type specific. Pain 156:428–438PubMedCrossRef
8.
Cui W, Li Y, Wang Z, Song C, Yu Y, Wang G, Li J, Wang C, Zhang L (2021) Spinal caspase-6 regulates AMPA receptor trafficking and dendritic spine plasticity through netrin-1 in postoperative pain after orthopedic surgery for tibial fracture in mice. Pain 162(1):124–134PubMedCrossRef
9.
Tang Y, Liu S, Shu H, Xing Y, Tao F (2018) AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain. Neuropharmacology 133:462–469PubMedPubMedCentralCrossRef
10.
Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63(1):182–217PubMedCrossRef
11.
Gee TA, Weintraub NC, Lu D, Phelps CE, Navratilova E, Heien ML, Porreca F (2020) A pain-induced tonic hypodopaminergic state augments phasic dopamine release in the nucleus accumbens. Pain 161(10):2376–2384PubMedPubMedCentralCrossRef
12.
El-Ghundi M, O’Dowd BF, George SR (2007) Insights into the role of dopamine receptor systems in learning and memory. Rev Neurosci 18(1):37–66
13.
Espadas I, Ortiz O, García-Sanz P, Sanz-Magro A, Alberquilla S, Solis O, Delgado-García JM, Gruart A, Moratalla R (2021) Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse. Cereb Cortex 31(4):2187–2204PubMedCrossRef
14.
Moreira FA, Dalley JW (2015) Dopamine receptor partial agonists and addiction. Eur J Pharmacol 752:112–115PubMedCrossRef
15.
Akerman S, Goadsby PJ (2005) The role of dopamine in a model of trigeminovascular nociception. J Pharmacol Exp Ther 314(1):162–169PubMedCrossRef
16.
Bergerot A, Storer RJ, Goadsby PJ (2007) Dopamine inhibits trigeminovascular transmission in the rat. Ann Neurol 61(3):251–262PubMedCrossRef
17.
Tang DL, Luan YW, Zhou CY, Xiao C (2021) D2 receptor activation relieves pain hypersensitivity by inhibiting superficial dorsal horn neurons in parkinsonian mice. Acta Pharmacol Sin 42(2):189–198PubMedCrossRef
18.
Zheng P, Su QP, Jin D, Yu Y, Huang XF (2020) Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons. Front Neurosci 14:642PubMedPubMedCentralCrossRef
19.
Jia JM, Zhao J, Hu Z, Lindberg D, Li Z (2013) Age-dependent regulation of synaptic connections by dopamine D2 receptors. Nat Neurosci 16(11):1627–1636PubMedPubMedCentralCrossRef
20.
Håkansson K, Galdi S, Hendrick J, Snyder G, Greengard P, Fisone G (2006) Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. J Neurochem 96(2):482–488PubMedCrossRef
21.
Liu P, Qin D, Lv H, Fan W, Tao Z, Xu Y (2021) Neuroprotective effects of dopamine D2 receptor agonist on neuroinflammatory injury in olfactory bulb neurons in vitro and in vivo in a mouse model of allergic rhinitis. Neurotoxicology 87:174–181PubMedCrossRef
22.
23.
Hsieh YS, Chen PN, Yu CH, Kuo DY (2014) Central dopamine action modulates neuropeptide-controlled appetite via the hypothalamic PI3K/NF-κB-dependent mechanism. Genes Brain Behav 13(8):784–793PubMedCrossRef
24.
Li T, Liu T, Chen X, Li L, Feng M, Zhang Y, Wan L, Zhang C, Yao W (2020) Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain. J Neuroinflammation 17(1):211PubMedPubMedCentralCrossRef
25.
Xie MJ, Ishikawa Y, Yagi H, Iguchi T, Oka Y, Kuroda K, Iwata K, Kiyonari H, Matsuda S, Matsuzaki H, Yuzaki M, Fukazawa Y, Sato M (2019) PIP3-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover. Sci Rep 9(1):4305PubMedPubMedCentralCrossRef
26.
Wigerblad G, Huie JR, Yin HZ, Leinders M, Pritchard RA, Koehrn FJ, Xiao WH, Bennett GJ, Huganir RL, Ferguson AR, Weiss JH, Svensson CI, Sorkin LS (2017) Inflammation-induced GluA1 trafficking and membrane insertion of Ca2+ permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A. Exp Neurol 293:144–158PubMedPubMedCentralCrossRef
27.
Liu YY, Jiao ZY, Li W, Tian Q (2017) PI3K/AKT signaling pathway activation in a rat model of migraine. Mol Med Rep 16(4):4849–4854PubMedCrossRef
28.
Pezet S, Marchand F, D’Mello R, Grist J, Clark AK, Malcangio M, Dickenson AH, Williams RJ, McMahon SB (2008) Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions. J Neurosci 28(16):4261–4270
29.
30.
Lei J, Ingbar DH (2011) Src kinase integrates PI3K/Akt and MAPK/ERK1/2 pathways in T3-induced Na-K-ATPase activity in adult rat alveolar cells. Am J Physiol Lung Cell Mol Physiol 301(5):L765–L771PubMedCrossRef
31.
Mao LM, Wang JQ (2016) Dopamine D2 receptors are involved in the regulation of Fyn and metabotropic glutamate receptor 5 phosphorylation in the rat striatum in vivo. J Neurosci Res 94(4):329–338PubMedPubMedCentralCrossRef
32.
Dai WL, Bao YN, Fan JF, Ma B, Li SS, Zhao WL, Yu BY, Liu JH (2020) Blockade of spinal dopamine D1/D2 receptor suppresses activation of NMDA receptor through Gαq and Src kinase to attenuate chronic bone cancer pain. J Adv Res 28:139–148PubMedPubMedCentralCrossRef
33.
Wang XY, Zhou HR, Wang S et al (2018) NR2B-Tyr phosphorylation regulates synaptic plasticity in central sensitization in a chronic migraine rat model. J Headache Pain 19(1):102 (Published 2018 Nov 6)PubMedPubMedCentralCrossRef
34.
Zeng X, Niu Y, Qin G, Zhang D, Zhou J, Chen L (2020) Deficiency in the function of inhibitory interneurons contributes to glutamate-associated central sensitization through GABABR2-SynCAM1 signaling in chronic migraine rats. FASEB J 34(11):14780–14798PubMedCrossRef
35.
Storer RJ, Supronsinchai W, Srikiatkhachorn A (2015) Animal models of chronic migraine. Curr Pain Headache Rep 19(1):467PubMedCrossRef
36.
Melo-Carrillo A, Lopez-Avila A (2013) A chronic animal model of migraine, induced by repeated meningeal nociception, characterized by a behavioral and pharmacological approach. Cephalalgia 33(13):1096–1105PubMedCrossRef
37.
Hoshino H, Obata H, Nakajima K, Mieda R, Saito S (2015) The antihyperalgesic effects of intrathecal bupropion, a dopamine and noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. Anesth Analg 120(2):460–466PubMedCrossRef
38.
Zha L, Yu Z, Fang J, Zhou L, Guo W, Zhou J (2020) NLRC3 Delays the Progression of AD in APP/PS1 Mice via Inhibiting PI3K Activation. Oxid Med Cell Longev 2020:5328031PubMedPubMedCentral
39.
Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32(1):77–88PubMedCrossRef
40.
Wang J, Fei Z, Liang J, Zhou X, Qin G, Zhang D, Zhou J, Chen L (2020) EphrinB/EphB Signaling Contributes to the Synaptic Plasticity of Chronic Migraine Through NR2B Phosphorylation. Neuroscience 21(428):178–191CrossRef
41.
Langlois SD, Morin S, Yam PT, Charron F (2010) Dissection and culture of commissural neurons from embryonic spinal cord. J Vis Exp 39:1773
42.
Henle F, Fischer C, Meyer DK, Leemhuis J (2006) Vasoactive intestinal peptide and PACAP38 control N-methyl-D-aspartic acid-induced dendrite motility by modifying the activities of Rho GTPases and phosphatidylinositol 3-kinases. J Biol Chem 281(34):24955–24969PubMedCrossRef
43.
Lin J, Zhang X, Li C, Zhang Y, Lu H, Chen J, Li Z, Yang X, Wu Z (2020) Evodiamine via targeting nNOS and AMPA receptor GluA1 inhibits nitroglycerin-induced migraine-like response. J Ethnopharmacol 254:112727PubMedCrossRef
44.
Cui W, Li Y, Wang Z et al (2021) Spinal caspase-6 regulates AMPA receptor trafficking and dendritic spine plasticity through netrin-1 in postoperative pain after orthopedic surgery for tibial fracture in mice. Pain 162(1):124–134PubMedCrossRef
45.
Todd C, Lagman-Bartolome AM, Lay C (2018) Women and Migraine: the Role of Hormones. Curr Neurol Neurosci Rep 18(7):42PubMedCrossRef
46.
Pavlovic JM, Akcali D, Bolay H, Bernstein C, Maleki N (2017) Sex-related influences in migraine. J Neurosci Res 95(1–2):587–593PubMedCrossRef
47.
Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd (2009) Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 10(5):447–485PubMedPubMedCentralCrossRef
48.
Cairns BE (2007) The influence of gender and sex steroids on craniofacial nociception. Headache 47(2):319–324PubMedCrossRef
49.
Akerman S, Goadsby PJ (2007) Dopamine and migraine: biology and clinical implications. Cephalalgia 27(11):1308–1314PubMedCrossRef
50.
DaSilva AF, Nascimento TD, Jassar H, Heffernan J, Toback RL, Lucas S, DosSantos MF, Bellile EL, Boonstra PS, Taylor JMG, Casey KL, Koeppe RA, Smith YR, Zubieta JK (2017) Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo. Neurology 88(17):1634–1641PubMedPubMedCentralCrossRef
51.
Zhang X, Wang Y, Zhang K, Sheng H, Wu Y, Wu H, Wang Y, Guan J, Meng Q, Li H, Li Z, Fan G, Wang Y (2021) Discovery of tetrahydropalmatine and protopine regulate the expression of dopamine receptor D2 to alleviate migraine from Yuanhu Zhitong formula. Phytomedicine 91:153702PubMedCrossRef
52.
Kissiwaa SA, Bagley EE (2018) Central sensitization of the spino-parabrachial-amygdala pathway that outlasts a brief nociceptive stimulus. J Physiol 596(18):4457–4473PubMedCentralCrossRef
53.
Liu W, Lv Y, Ren F (2018) PI3K/Akt Pathway is Required for Spinal Central Sensitization in Neuropathic Pain. Cell Mol Neurobiol 38(3):747–755PubMedCrossRef
54.
Leinders M, Koehrn FJ, Bartok B, Boyle DL, Shubayev V, Kalcheva I, Yu NK, Park J, Kaang BK, Hefferan MP, Firestein GS, Sorkin LS (2014) Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: potential roles in acute inflammatory pain. Pain 155(6):1150–1160PubMedPubMedCentralCrossRef
55.
56.
Ji RR, Nackley A, Huh Y, Terrando N, Maixner W (2018) Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology 129(2):343–366PubMedCrossRef
57.
Bliss TV, Collingridge GL, Kaang BK, Zhuo M (2016) Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 17(8):485–496PubMedCrossRef
58.
Mateos-Aparicio P, Rodríguez-Moreno A (2020) Calcium Dynamics and Synaptic Plasticity. Adv Exp Med Biol 1131:965–984PubMedCrossRef
59.
Amici M, Doherty A, Jo J, Jane D, Cho K, Collingridge G, Dargan S (2009) Neuronal calcium sensors and synaptic plasticity. Biochem Soc Trans 37(Pt 6):1359–1363PubMedCrossRef
60.
Wang M, Ramasamy VS, Kang HK, Jo J (2020) Oleuropein promotes hippocampal LTP via intracellular calcium mobilization and Ca2+-permeable AMPA receptor surface recruitment. Neuropharmacology 176:108196PubMedCrossRef
61.
Bhardwaj A, Bhardwaj R, Dhawan DK, Kaur T (2019) Exploring the Effect of Endoplasmic Reticulum Stress Inhibition by 4-Phenylbutyric Acid on AMPA-Induced Hippocampal Excitotoxicity in Rat Brain. Neurotox Res 35(1):83–91PubMedCrossRef
62.
Nakajima C, Kulik A, Frotscher M, Herz J, Schäfer M, Bock HH, May P (2013) Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes. J Biol Chem 288(30):21909–21923PubMedPubMedCentralCrossRef
Metadata
Title
Dopamine receptor D2 regulates GLUA1-containing AMPA receptor trafficking and central sensitization through the PI3K signaling pathway in a male rat model of chronic migraine
Authors
Wei Zhang
Ming Lei
Qianwen Wen
Dunke Zhang
Guangcheng Qin
Jiying Zhou
Lixue Chen
Publication date
01-12-2022
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-022-01469-x

Other articles of this Issue 1/2022

The Journal of Headache and Pain 1/2022 Go to the issue

Research

Does MIDAS reduction at 3 months predict the outcome of erenumab treatment? A real-world, open-label trial

Research article

Early response to eptinezumab indicates high likelihood of continued response in patients with chronic migraine

Research article

Insulin sensitizes neural and vascular TRPV1 receptors in the trigeminovascular system

Research

Persistent headache after first-ever ischemic stroke: clinical characteristics and factors associated with its development

Research article

Assessment of peripheral biomarkers potentially involved in episodic and chronic migraine: a case-control study with a focus on NGF, BDNF, VEGF, and PGE2

Research article

Single-Pulse Transcranial Magnetic Stimulation for the preventive treatment of difficult-to-treat migraine: a 12-month prospective analysis