Alkali Burn Induced Corneal Spontaneous Pain and Activated Neuropathic Pain Matrix in the Central Nervous System in Mice

Xiang, Yan; Zhou, Wenchang; Wang, Ping; Yang, Hui; Gao, Feng; Hong-bin, Xiang; Manyande, Anne; Tian, Yuan; Tian, Xiaojing

doi:10.1097/ico.0000000000001336

Cited by 22 publications

(18 citation statements)

References 31 publications

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“…Tissue injury and remodeling beyond the ocular surface including retinal and optic nerve gliosis also have been reported after alkali injury to the cornea 26,28–31. Although alkali burn causes corneal nerve damage and significant pain in patients, little is known about the long-term effects of alkali burn injury to the oculo-trigeminal sensory system 32. In this study, we repurposed this injury model to study ocular sensitivity by combining CSI with application of NaCl to the cornea.…”

Section: Discussionmentioning

confidence: 99%

Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain

Cho

Bell

Botzet

et al. 2019

Trans. Vis. Sci. Tech.

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Purpose Chronic ocular pain is poorly understood and difficult to manage. We developed a murine model of corneal surface injury (CSI)–induced chronic ocular neuropathic pain. The study focuses on changes in corneal nerve morphology and associated short- and long-term pain-like behavior after CSI. Methods CSI was induced in mice by local application of an alkali solution (0.75 N NaOH). Corneal nerve architecture, morphology, density, and length were studied. Eye-wiping was evaluated before and after CSI in response to hypertonic saline (2 M NaCl). Naltrexone (NTX) or Naloxone-methiodide (NLX-me), opioid receptor antagonists, were given subcutaneously (s.c., 3 mg/kg) or topically (eye drop, 100 μM), and then an eye-wiping test was performed. Results CSI caused partial corneal deinnervation followed by gradual reinnervation. Regenerated nerves displayed increased tortuosity, beading, and branching. CSI enhanced hypertonic saline-induced eye-wiping behavior compared to baseline or sham-injury ( P < 0.01). This hypersensitivity peaked at 10 days and subsided 14 days after CSI. Administration of NTX, or NLX-me, a selective peripheral opioid antagonist, reinstated eye-wiping behavior in the injury group, but not in the sham groups ( P < 0.05). Conclusions This study introduces a model of chronic ocular pain and corneal neuropathy following CSI. CSI induces central and peripheral opioid receptor-dependent latent sensitization (LS) that is unmasked by systemic or topical administration of opioid antagonists. Translational Relevance This model of chronic ocular pain establishes LS as a new inhibitory mechanism in the oculotrigeminal system and may be used for potential diagnostic and therapeutic interventions for ocular neuropathy.

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Section: Discussionmentioning

confidence: 99%

Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain

Cho

Bell

Botzet

et al. 2019

Trans. Vis. Sci. Tech.

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“…They have been limited in that they have only shown an increase in spontaneous activity and decreases in chemical and mechanical responses inside the wound area after photorefractive surgery in the anaesthetized cat (Gallar et al, 2007). By using von Frey filaments and eye-wiping test to evaluate mechanical and chemical corneal sensitivity, respectively (Farazifard et al, 2005;Launay et al, 2016;Xiang et al, 2017;Zagon, Sassani, Immonen, & McLaughlin, 2014), we reported that topical 0.02% BAK instillation significantly increased both mechanical and chemical sensitivity, in accordance with a previous study from our laboratory (Launay et al, 2016). On the other hand, only an increase in chemical sensitivity was observed after corneal scraping.…”

Section: Discussionmentioning

confidence: 99%

Effects of corneal injury on ciliary nerve fibre activity and corneal nociception in mice: A behavioural and electrophysiological study

Joubert

Acosta

Gallar

et al. 2018

European Journal of Pain

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Background Ocular surface diseases are among the most frequent ocular pathologies. Ocular pain following corneal injury is frequently observed in clinic. Corneal sensory innervation is supplied by ciliary nerves derived from ophthalmic division of the trigeminal ganglion. Methods & Results Extracellular activity of the mouse ciliary nerve was first used to investigate the corneal responsiveness to chemical, mechanical and thermal stimulations in order to specifically study the responses of polymodal nociceptors, mechano‐nociceptors and cold thermoreceptor in a control cornea. Then, in two models of corneal injury (repeated instillations of 0.02% benzalkonium chloride and corneal scraping), we first measured the corneal sensitivity to chemical (eye‐wiping test) and mechanical (von Frey filaments) stimulation. Thereafter, we evaluated whether these corneal injuries modified the spontaneous and chemical stimulation‐evoked activity of the ciliary nerve. Both models of injury induced a significant corneal chemical hypersensitivity correlated with an increase of the spontaneous activity of the ciliary nerve and a faster response of the ciliary nerve after a chemical stimulation. Conclusions Overall, this study provides new insights into the functional aspects of corneal nerve fibre activity in mice after corneal injury. The increase in ciliary nerve activity may thus contribute to the development of ocular pain after corneal damage. Significance This study highlights the parallel increase in ciliary nerve activity and corneal sensitivity after corneal injury in mice. The strategy of combining ex vivo electrophysiological recordings of the ciliary nerve in mice and corneal sensitivity measurements therefore helps to uncover the functional aspects of corneal pain.

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“… 3 A previous study in mice demonstrated that corneal pain could lead to neuronal activation in the spinal trigeminal nucleus, insular cortex, and anterior cingulated cortex. 4 Meanwhile, a study involving neuroimaging research indicated that corneal pain in patients appeared to be associated with activation of the primary somatosensory cortex. 5 Furthermore, EP has been frequently shown to be accompanied by mental disorders.…”

Section: Introductionmentioning

confidence: 99%

Assessment of synchronous neural activities revealed by regional homogeneity in individuals with acute eye pain: a resting-state functional magnetic resonance imaging study

Tang

Huang

et al. 2018

JPR

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ObjectivePrevious neuroimaging studies have demonstrated that pain-related diseases are associated with brain function and anatomical abnormalities, whereas altered synchronous neural activity in acute eye pain (EP) patients has not been investigated. The purpose of this study was to explore whether or not synchronous neural activity changes were measured with the regional homogeneity (ReHo) method in acute EP patients.MethodsA total of 20 patients (15 males and 5 females) with EP and 20 healthy controls (HCs) consisting of 15 and 5 age-, sex-, and education-matched males and females, respectively, underwent resting-state functional magnetic resonance imaging. The ReHo method was applied to assess synchronous neural activity changes.ResultsCompared with HCs, acute EP patients had significantly lower ReHo values in the left precentral/postcentral gyrus (Brodmann area [BA]3/4), right precentral/postcentral gyrus (BA3/4), and left middle frontal gyrus (BA6). In contrast, higher ReHo values in acute EP patients were observed in the left superior frontal gyrus (BA11), right inferior parietal lobule (BA39/40), and left precuneus (BA7). However, no relationship was found between the mean ReHo signal values of the different areas and clinical manifestations, which included both the duration and degree of pain in EP patients.ConclusionOur study highlighted that acute EP patients showed altered synchronous neural activities in many brain regions, including somatosensory regions. These findings might provide useful information for exploration of the neural mechanisms underlying acute EP.

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Alkali Burn Induced Corneal Spontaneous Pain and Activated Neuropathic Pain Matrix in the Central Nervous System in Mice

Abstract: Alkali burn could cause corneal spontaneous pain and activate the neuropathic pain matrix in the central nervous system. Furthermore, activation of ERK in the ACC is required for alkali burn induced corneal spontaneous pain.

Cited by 22 publications

References 31 publications

Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain

Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain

Effects of corneal injury on ciliary nerve fibre activity and corneal nociception in mice: A behavioural and electrophysiological study

Assessment of synchronous neural activities revealed by regional homogeneity in individuals with acute eye pain: a resting-state functional magnetic resonance imaging study

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