ArticleHeadache
Episodic dural stimulation in awake rats: a model for recurrent headache.
Article in Headache. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers, 1 of them a synthesis that pooled it.
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Who cites it
118 citing papers in PubMed, 1 synthesis or guideline pooled it, 234 citations in OpenAlex.
- Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon.Cephalalgia : an international journal of headache · 2019Pooled it
- Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation: the MOXY Study.Journal of translational medicine · 2019Trial
- From bench to bedside: relevant animal models across the migraine attack phases.The journal of headache and pain · 2026Review
- Refractory Neuropathic Pain in the Head and Neck: Neuroanatomical and Clinical Significance of the Cervicotrigeminal Complex.Life (Basel, Switzerland) · 2025Review
- Unmasking the relationship between CGRP and glutamate: from peripheral excitation to central sensitization in migraine.The journal of headache and pain · 2025Review
- Sex differences in the effects of calcitonin gene-related peptide signaling on migraine-like behavior in animal models: a narrative review.Frontiers in neurology · 2025Review
- Meningeal brain borders and migraine headache genesis.Trends in neurosciences · 2024Review
- Animal Models of Chronic Migraine: From the Bench to Therapy.Current pain and headache reports · 2024Review
- The role of kynurenines in migraine-related neuroimmune pathways.The journal of headache and pain · 2024Review
- Unraveling the interplay of neuroinflammatory signaling between parenchymal and meningeal cells in migraine headache.The journal of headache and pain · 2024Review
- Pathology of pain and its implications for therapeutic interventions.Signal transduction and targeted therapy · 2024Review
- Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats.The journal of headache and pain · 2024Article
- Extrasynaptic δGABAA receptors mediate resistance to migraine-like phenotype in rats.The journal of headache and pain · 2024Article
- Models of Trigeminal Activation: Is There an Animal Model of Migraine?Brain sciences · 2024Review
- Potential mechanisms for osteopathic manipulative treatment to alleviate migraine-like pain in female rats.Frontiers in pain research (Lausanne, Switzerland) · 2024Article
- Meningeal Mechanisms and the Migraine Connection.Annual review of neuroscience · 2023Review
- SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1α positive feedback loop.The journal of headache and pain · 2023Article
- Activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in a chronic migraine rat model.The journal of headache and pain · 2023Article
- Electroacupuncture at Fengchi(GB20) and Yanglingquan(GB34) Ameliorates Paralgesia through Microglia-Mediated Neuroinflammation in a Rat Model of Migraine.Brain sciences · 2023Article
- Hangover headache and its behavioral changes in rats.Iranian journal of basic medical sciences · 2023Article
58 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
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Abstract
objectivesTo model, in rats, the development of chronic trigeminal nociceptive hypersensitivity seen in patients with recurrent headache.
backgroundPathophysiology studies suggest that patients with recurrent migraine headache experience repeated bouts of dural nociceptor activation. In some patients, the severity and frequency of headache attacks increase over time. Patients with recurrent headache are hypersensitive to nitric oxide donors, such as glyceryl trinitrate (GTN). Current trigeminal pain models do not reflect the repeated episodic nature of dural nociceptor activation in patients with recurrent headache. Repeated nociceptor activation creates long-lasting changes in the periphery and brain due to activity-dependent neuronal plasticity. An animal model of repeated activation of dural nociceptors will facilitate the study of the physiological changes caused by repeated, episodic pain and the factors important for the transition of episodic to chronic migraine.
methodsWe induced dural inflammation by infusing an inflammatory soup (IS) through a cannula on the dura in awake behaving rats. This was repeated 3 times per week for up to 4 weeks. Periorbital pressure sensory testing was used to monitor the change in trigeminal sensitivity. Rats were challenged with GTN to test the hypothesis that many dural stimulations are required to model the hypersensitivity of migraine patients. Quantitative trigeminal sensory testing and microdialysis in the trigeminal nucleus caudalis (TNC) were used to measure GTN hypersensitivity.
resultsMultiple infusions of IS (>8), over weeks, induced a long-lasting decrease in periorbital pressure thresholds that lasted >3 weeks after the last infusion. In contrast, IS infusion in IS-naive rats and those that received 3 IS infusions produced only short-lasting decreases in periorbital pressure thresholds. Rats that received more than 8 IS infusions showed a marked increase in their neurochemical and behavioral responses to GTN. In these rats, GTN induced a decrease in periorbital von Frey thresholds that lasted >5 hours. In contrast, in rats that received only 3 IS infusions, GTN caused a threshold decrease for 1.5 hour. In vivo microdialysis in the TNC showed that GTN increased extracellular glutamate levels in rats with more than 8 IS infusions to 7.7 times the basal levels. In IS-naive rats and those that received only 3 IS infusions, the extracellular glutamate levels rose to only 1.7 and 1.9 times the basal level, respectively.
conclusionsRepeated IS stimulation of the dura produces a chronic state of trigeminal hypersensitivity and potentiates the response to GTN. This hyperresponsiveness outlasts the last IS infusion and is the basis of our rat model of recurrent headache. This model can be used to study the changes in the brain and periphery induced by repeated trigeminovascular nociceptor activation and has the potential to elucidate the mechanisms for the transition of episodic to chronic headache.
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