Dry eye disease (DED) affects nearly 55% of people worldwide; several studies have proposed that central sensitization and neuroinflammation may contribute to the developing corneal neuropathic pain of DED, while the underlying mechanisms of this contribution remain to be investigated. Excision of extra orbital lacrimal glands established the dry eye model. Corneal hypersensitivity was examined through chemical and mechanical stimulation, and open field test measured the anxiety levels. Restingstate fMRI is a method of functional magnetic resonance imaging (rs‐fMRI) was performed for anatomical involvement of the brain regions. The amplitude of low‐frequency fluctuation (ALFF) determined brain activity. Immunofluorescence testing and Quantitative real‐time polymerase chain reaction were also performed to further validate the findings. Compared with the Sham group, ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were increased in the dry eye group. This change of ALFF in the insular cortex was linked with the increment in corneal hypersensitivity (p < 0.01), c‐Fos (p < 0.001), brain‐derived neurotrophic factor (p < 0.01), TNF‐α, IL‐6, and IL‐1β (p < 0.05). In contrast, IL‐10 levels (p < 0.05) decreased in the dry eye group. DED‐induced corneal hypersensitivity and upregulation of inflammatory cytokines could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin‐B (p < 0.01) without affecting anxiety levels. Our study reveals that the functional activity of the brain associated with corneal neuropathic pain and neuroinflammation in the insular cortex might contribute to dry eye‐related corneal neuropathic pain.
Purpose:Chronic corneal pain is the most common symptom of dry eye
disease (DED), while the central sensitization mechanisms underlying
remain unclear. Methods:Excision of extra orbital lacrimal glands was
used to establish dry eye (DE) model. Tear volume measurements, corneal
fluorescein staining, corneal hypersensitivity and anxiety behavior were
tested after surgery. The amplitude of low-frequency fluctuation (ALFF)
by fMRI was used for determining brain functional activity. C-Fos,
Brain-derived neurotrophic factor (BDNF), and cytokine levels in
corresponding brain regions were tested. Results:Compared to the Sham
group, the ALFF signals in the supplemental somatosensory area,
secondary auditory cortex, agranular insular cortex, temporal
association areas, and ectorhinal cortex brain areas were enhanced in DE
group. ALFF signal in the insular cortex was related to corneal
hypersensitivity (p < 0.01). C-Fos (P < 0.001), BDNF
(P < 0.01), TNF-α, IL-6 and IL-1β (P < 0.05)
increased, while IL-10 levels (P < 0.05) decreased in the
insular cortex in the DE group. Surgery-induced corneal hypersensitivity
and upregulation of inflammatory cytokines, but not anxiety, could be
blocked by insular cortex injection of Tyrosine Kinase receptor B (TrkB)
agonist cyclotraxin-B (P< 0.01). Conclusions :This research
presents the map of functional brain by ALFF through rs-fMRI associated
with chronic corneal pain. BDNF-TrkB signaling-related neuroinflammation
in the insular cortex might contribute to dry eye-related chronic
corneal pain. This measure could potentially help clinicians improve
therapeutic approach to pain control and development of diagnostic
approach.
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