Alteration of neural activity and neuroinflammatory factors in the insular cortex of mice with corneal neuropathic pain

Abstract

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.

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

“…For instance, central corneal neuropathic pain is reportedly associated with lower corneal esthesiometry results compared to peripheral corneal neuropathic pain and people without neuropathic pain (Leonardi et al, 2023). Furthermore, functional magnetic resonance imaging (fMRI) has also been used in studying corneal neuropathic pain, just like trigeminal neuralgia; hence, it may help to diagnose corneal neuropathic pain (Choudhury et al, 2022;Xu et al, 2023). A recent study has shown greater activity in fMRI in people with corneal neuropathic pain compared to healthy controls (Choudhury et al, 2022).…”

“…The interaction between proinflammatory neuropeptides and pain-stimulating cytokines establishes feedback, enabling the continuation of both inflammation and pain, commonly referred to as neuropathic pain. Corneal nerve injury interferes with the transmission of these receptors to the trigeminal ganglion and the projections to the thalamus and somatosensory cortex, instigating sensations of pain and discomfort (Choudhury et al, 2022;Xu et al, 2023;Yan et al, 2020). Apart from inflammation enhancing the activity of existing receptors via phosphorylation, it also causes the de novo transcription of additional ion channels (Goldstein et al, 2019;Sachs et al, 2002;Tran et al, 2000).Altered signaling of many channels, including voltage-gated sodium (Nav1.7-1.9), potassium, and calcium channels, issues downstream effector pathways.…”

“…People with corneal neuropathic pain exhibit more significant activity in the visual, insular, primary somatosensory (S1), and anterior mid‐cingulate (aMCC) cortices (Choudhury et al., 2022; Xu et al., 2023). Even after administration of topical anesthetic in people with corneal neuropathic pain, the topical anesthesia decreased activation within regions of S1 and anterior mid‐cingulate but not in the visual cortex or insula (Choudhury et al., 2022; Xu et al., 2023).…”

“…Peripheral sensitization may result in central sensitization, which is responsible for the hyperexcitability of neurons in the central nervous system (Belmonte et al., 2017). When the cornea nerves are activated, it facilitates the release of neuromediators that, in turn, promote immune cell recruitment, such as dendritic cells and their activation, a complex process commonly occurring referred to as neurogenic inflammation (Asiedu, 2022; Xu et al., 2023). When these leukocytes arrive at the injury site, they promote the production and release of pain modulators and pain‐enhancing molecules such as cytokine, chemokines, neurokines, growth factors, and neuropeptides (Asiedu, 2022; López‐de la Rosa et al., 2021).…”

“…Similar investigations showed distinct changes in the neuroanatomy of synapses in the spinal trigeminal subnucleus caudalis and other higher brain centers comprising the insula, thalamus, and cerebral cortex (Zayan et al., 2020). People with corneal neuropathic pain exhibit more significant activity in the visual, insular, primary somatosensory (S1), and anterior mid‐cingulate (aMCC) cortices (Choudhury et al., 2022; Xu et al., 2023). Even after administration of topical anesthetic in people with corneal neuropathic pain, the topical anesthesia decreased activation within regions of S1 and anterior mid‐cingulate but not in the visual cortex or insula (Choudhury et al., 2022; Xu et al., 2023).…”