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 1/2024

Open Access 01-12-2024 | Nitroglycerin | Research

Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice

Authors: Lei Wang, Xiaoming Liu, Chenlu Zhu, Shouyi Wu, Zhilei Li, Lipeng Jing, Zhenchang Zhang, Yuhong Jing, Yonggang Wang

Published in: The Journal of Headache and Pain | Issue 1/2024

Login to get access

Abstract

Background

Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM.

Methods

A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated.

Results

Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE.

Conclusion

EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.
Literature
1.
(2019) Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the global burden of disease study 2016. The Lancet Neurology 18(5):459–480
2.
Schwedt TJ (2014) Chronic migraine. BMJ (Clinical research ed) 348:g1416PubMed
3.
4.
5.
6.
7.
8.
He W, Long T, Pan Q, Zhang S, Zhang Y, Zhang D et al (2019) Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model. J Neuroinflammation 16(1):78PubMedPubMedCentralCrossRef
9.
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
10.
van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1(3):191–198PubMedCrossRef
11.
Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7(9):697–709PubMedCrossRef
12.
Kimura LF, Sant'Anna MB, Zambelli VO, Giardini AC, Jared SGS, Antoniazzi MM et al (2020) Early exposure to environmental enrichment protects male rats against neuropathic pain development after nerve injury. Exp Neurol 332:113390PubMedCrossRef
13.
Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM et al (2005) Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120(5):701–713PubMedCrossRef
14.
Kempermann G (2019) Environmental enrichment, new neurons and the neurobiology of individuality. Nat Rev Neurosci 20(4):235–245PubMedCrossRef
15.
Seo JH, Kang SW, Kim K, Wi S, Lee JW, Cho SR (2020) Environmental enrichment attenuates oxidative stress and alters detoxifying enzymes in an A53T alpha-Synuclein transgenic mouse model of Parkinson's disease. Antioxidants (Basel) 9(10)
16.
Zhou F, Chen C, Huang Y, Hu H, Li L, Tan Y (2018) The effects of enriched environmental intervention on the parturition outcome and filial health of pregnant mice with chronic pain. Biol Res Nurs 20(3):264–271PubMedCrossRef
17.
Tai WL, Sun L, Li H, Gu P, Joosten EA, Cheung CW (2021) Additive effects of environmental enrichment and ketamine on neuropathic pain relief by reducing glutamatergic activation in spinal cord injury in rats. Front Neurosci 15:635187PubMedPubMedCentralCrossRef
18.
Ahn N, Roh S, Park J (2021) The status and issues of the institutional animal care and use Committee of Seoul National University: from its establishment to the present day. Exp Anim 70(4):532–540PubMedPubMedCentralCrossRef
19.
Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A (2014) Characterization of a novel model of chronic migraine. Pain 155(2):269–274PubMedCrossRef
20.
Wang F, Jiang W, Gao L, Liu C, Deng M, Ren X et al (2021) Detecting abnormal neuronal activity in a chronic migraine model by Egr1-EGFP transgenic mice. Front Neurosci 15:705938PubMedPubMedCentralCrossRef
21.
Christensen SL, Hansen RB, Storm MA, Olesen J, Hansen TF, Ossipov M et al (2020) Von Frey testing revisited: provision of an online algorithm for improved accuracy of 50% thresholds. European journal of pain (London, England) 24(4):783–790PubMedCrossRef
22.
23.
Burstein R, Cutrer MF, Yarnitsky D (2000) The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain J Neurol 123(Pt 8):1703–1709CrossRef
24.
Dodick D, Silberstein S (2006) Central sensitization theory of migraine: clinical implications. Headache 46(Suppl 4):S182–S191PubMed
25.
26.
Ashina M, Hansen JM, Bo ÁD, Olesen J (2017) Human models of migraine - short-term pain for long-term gain. Nat Rev Neurol 13(12):713–724PubMedCrossRef
27.
Reuter U (2018) GBD 2016: still no improvement in the burden of migraine. The Lancet Neurology 17(11):929–930PubMedCrossRef
28.
Bates EA, Nikai T, Brennan KC, Fu YH, Charles AC, Basbaum AI et al (2010) Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 30(2):170–178PubMedPubMedCentralCrossRef
29.
30.
Wu S, Ren X, Zhu C, Wang W, Zhang K, Li Z et al (2022) A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine. The journal of headache and pain 23(1):128PubMedPubMedCentralCrossRef
31.
Long T, He W, Pan Q, Zhang S, Zhang Y, Liu C et al (2018) Microglia P2X4 receptor contributes to central sensitization following recurrent nitroglycerin stimulation. J Neuroinflammation 15(1):245PubMedPubMedCentralCrossRef
32.
May A, Schulte LH (2016) Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol 12(8):455–464PubMedCrossRef
33.
Falkowska M, Ntamati NR, Nevian NE, Nevian T, Acuna MA (2023) Environmental enrichment promotes resilience to neuropathic pain-induced depression and correlates with decreased excitability of the anterior cingulate cortex. Front Behav Neurosci 17:1139205PubMedPubMedCentralCrossRef
34.
Vachon P, Millecamps M, Low L, Thompsosn SJ, Pailleux F, Beaudry F et al (2013) Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain. Behavioral and brain functions : BBF 9:22PubMedPubMedCentralCrossRef
35.
Eftekhari S, Edvinsson L (2011) Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 12:112PubMedPubMedCentralCrossRef
36.
Zhang Y, Zhang Y, Tian K, Wang Y, Fan X, Pan Q et al (2020) Calcitonin gene-related peptide facilitates sensitization of the vestibular nucleus in a rat model of chronic migraine. The journal of headache and pain 21(1):72PubMedPubMedCentralCrossRef
37.
Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ (2001) Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 21(14):5027–5035PubMedPubMedCentralCrossRef
38.
Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28(20):5189–5194PubMedPubMedCentralCrossRef
39.
Ferrari MD, Goadsby PJ, Burstein R, Kurth T, Ayata C, Charles A et al (2022) Migraine. Nat Rev Dis Prim 8(1):2PubMedCrossRef
40.
O’Hare L, Tarasi L, Asher JM, Hibbard PB, Romei V (2023) Excitation-inhibition imbalance in migraine: from neurotransmitters to brain oscillations. Int J Mol Sci 24(12)
41.
Al-Karagholi MA, Ghanizada H, Nielsen CAW, Hougaard A, Ashina M (2021) Opening of ATP sensitive potassium channels causes migraine attacks with aura. Brain J Neurol 144(8):2322–2332CrossRef
42.
43.
Fremeau RT Jr, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ et al (2001) The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31(2):247–260PubMedCrossRef
44.
Hafner AS, Donlin-Asp PG, Leitch B, Herzog E, Schuman EM (2019) Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science 364(6441)
45.
Leiguarda C, McCarthy CJ, Casadei M, Lundgren KH, Coronel MF, Trigosso-Venario H et al (2020) Transcript expression of vesicular glutamate transporters in rat dorsal root ganglion and spinal cord neurons: impact of spinal blockade during Hindpaw inflammation. ACS Chem Neurosci 11(17):2602–2614PubMedCrossRef
46.
Loken LS, Braz JM, Etlin A, Sadeghi M, Bernstein M, Jewell M et al (2021) Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity. Elife 10
47.
Zhang FX, Ge SN, Dong YL, Shi J, Feng YP, Li Y et al (2018) Vesicular glutamate transporter isoforms: the essential players in the somatosensory systems. Prog Neurobiol 171:72–89PubMedCrossRef
Metadata
Title
Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice
Authors
Lei Wang
Xiaoming Liu
Chenlu Zhu
Shouyi Wu
Zhilei Li
Lipeng Jing
Zhenchang Zhang
Yuhong Jing
Yonggang Wang
Publication date
01-12-2024
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2024
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-024-01779-2

Other articles of this Issue 1/2024

The Journal of Headache and Pain 1/2024 Go to the issue

Research

Dynamic changes in glymphatic function in reversible cerebral vasoconstriction syndrome

Review

Health equity, care access and quality in headache – part 1

Research

Trends and prescribing patterns of antimigraine medicines in nine major cities in China from 2018 to 2022: a retrospective prescription analysis

Research

Real-world effectiveness and satisfaction with intravenous eptinezumab treatment in patients with chronic migraine: REVIEW, an observational, multi-site, US-based study

Research

Does pain self-efficacy predict, moderate or mediate outcomes in people with chronic headache; an exploratory analysis of the CHESS trial

Research

Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats