Effects of Mirogabalin on Hyperalgesia and Chronic Ocular Pain in Tear-Deficient Dry-Eye Rats.

Purpose: Patients with dry eye disease (DED) sometimes complain of ocular pain. DED-related ocular pain has many similarities with neuropathic pain. Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is approved for treating neuropathic pain in Japan. This study aimed to investigate the effect of mirogabalin on hyperalgesia and chronic ocular pain in a rat DED model. Methods: DED was induced in female Sprague Dawley rats by unilaterally excising the external lacrimal gland (ELG) and Harderian gland (HG). After 4 weeks of ELG and HG removal, tear production (pH threads) and corneal epithelial damage (fluorescein staining) were evaluated. Corneal hyperalgesia and chronic pain were analyzed, respectively, by measuring capsaicin-induced eye-wiping behavior and c-Fos expression in the trigeminal nucleus. Mirogabalin (10 or 3 mg/kg) was evaluated for effects on DED-induced hyperalgesia and chronic ocular pain. Results: Tear production was significantly lower in DED-induced eyes than in control eyes. Corneal damage was significantly higher in DED eyes than in control eyes. Hyperalgesia and chronic ocular pain were detected 4 weeks after ELG and HG removal. Five days of mirogabalin administration significantly suppressed capsaicin-induced eye-wiping behavior, which indicated the suppression of ocular hyperalgesia. Administration of 10 mg/kg mirogabalin significantly reduced c-Fos expression in the trigeminal nucleus, which indicated the amelioration of chronic ocular pain. Conclusions: Mirogabalin suppressed DED-induced hyperalgesia and chronic ocular pain in a rat DED model. Our findings suggested that mirogabalin might effectively alleviate chronic ocular pain in patients with DED.

Optogenetic Inhibition of Nav1.8 Expressing Corneal Afferents Reduces Persistent Dry Eye Pain.

Purpose: The aim of the present study was to investigate the contribution of Nav1.8 expressing corneal afferent neurons to the presence of ongoing pain in lacrimal gland excision (LGE)-induced dry eye. Methods: The proton pump archaerhodopsin-3/eGFP (ArchT/eGFP) was conditionally expressed in corneal afferents using Nav1.8-cre mice. Dry eye was produced by unilateral LGE. Real time place preference was assessed using a three-chamber apparatus. A neutral, unlit center chamber was flanked by one illuminated with a control light and one illuminated with an ArchT activating light. For real-time preference, animals were placed in the neutral chamber and tracked over five 10-minute sessions, with the lights turned on during the second and fourth sessions. In other studies, movement was tracked over three 10-minute sessions (the lights turned on only during the second session), with animals tested once per day over the course of 4 days. A local anesthetic was used to examine the role of ongoing corneal afferent activity in producing place preference. Results: The corneal afferent nerves and trigeminal ganglion cell bodies showed a robust eGFP signal in Nav1.8-cre;ArchT/eGFP mice. After LGE, Nav1.8-cre;ArchT/eGFP mice demonstrated a preference for the ArchT activating light paired chamber. Preference was prevented with pre-application to the cornea of a local anesthetic. Nav1.8-cre;ArchT/eGFP mice with sham surgery and LGE wild-type control mice did not develop preference. Conclusions: Results indicate LGE-induced persistent, ongoing pain, driven by Nav1.8 expressing corneal afferents. Inhibition of these neurons represents a potential strategy for treating ongoing dry eye-induced pain.

Tear Opiorphin Levels in Ocular Pain Caused by Corneal Foreign Body.

PURPOSE: Opiorphin is an endogenous inhibitor of enkephalin-degrading enzymes. It has a strong analgesic effect in chemical and mechanical pain models. We aimed to evaluate the tear opiorphin levels in ocular pain caused by corneal foreign bodies and demonstrate whether there is any correlation with pain levels obtained from the Visual Analog Scale (VAS) score and tear opiorphin level. METHODS: Thirty-two healthy individuals and 34 individuals diagnosed with corneal foreign bodies were included in this study. Tear opiorphin levels were measured by the ELISA method using a commercially available kit. The difference in tear opiorphin levels between the patient and control groups were evaluated using the Mann-Whitney U test. The correlation between VAS scores and tear opiorphin levels was evaluated using the Spearman rank correlation coefficient. RESULTS: The median values of tear opiorphin levels of the patient and control groups were 134 pg/mL (86.86-296.25) and 109.80 pg/mL (66.15-191.49), respectively. The Mann-Whitney U test showed a statistically significant difference in tear opiorphin levels between patient and control groups (P < 0.05). No ocular pain was reported in the control group. The median VAS score of the patient group was 6 points (1-9). No correlation was found between VAS scores and tear opiorphin levels in the patient group. CONCLUSIONS: The cornea is the most densely innervated tissue, and the highest opiorphin concentrations have been observed in tear. It is, therefore, expected that the stimulation or damage to the nerve endings in cornea would cause an increase in opiorphin secretion as a pain relief mechanism.

Lacrimal Gland Denervation Alters Tear Protein Composition and Impairs Ipsilateral Eye Closures and Corneal Nociception.

Purpose: To evaluate spontaneous and evoked ocular sensory responses in rats after denervation of the lacrimal gland, as well as protein changes in tears that may mediate functional changes. Methods: Sprague-Dawley rats served as subjects. The left lacrimal gland was partially denervated with saporin toxin conjugated to p75. Unilateral and bilateral eye closures (winks and blinks) and grooming behaviors were measured weekly. Nociceptive responses were evoked by ocular application of menthol; tear production was assessed using the phenol thread test. Relative changes in tear protein abundances were measured using a Tandem Mass Tagging approach. Results: Denervation of the lacrimal gland reduced eye closure behavior, particularly in the ipsilateral eye, and eye wipe responses to noxious menthol were also reduced. Tear volume did not change, but tear protein composition was altered. Proteins implicated in the structural integrity of epithelial cells and in protective functions were reduced by lacrimal denervation, including keratins, serotransferrin, and beta-defensin. Other proteins that may modulate TRPM8 channels and alter sensory neuronal function were reduced, including arachidonate 15-lipoxygenase B. A low-abundance protein that responds to oxidative stress and injury, proteasome subunit beta type 10, was upregulated in denervated rats. Conclusions: Denervation of the lacrimal gland causes long-lasting hypoalgesia, impairs the blink response, and alters tear proteins. Tear proteins were altered without changing tear volume. We speculate that impaired TRPM8 function in corneal sensory nerves may contribute to ocular hypoalgesia, supporting growing evidence that this transduction molecule is important for both nociceptive and spontaneous blinking behaviors.

Corneal Mechanical Thresholds Negatively Associate With Dry Eye and Ocular Pain Symptoms.

PURPOSE: To examine associations between corneal mechanical thresholds and metrics of dry eye. METHODS: This was a cross-sectional study of individuals seen in the Miami Veterans Affairs eye clinic. The evaluation consisted of questionnaires regarding dry eye symptoms and ocular pain, corneal mechanical detection and pain thresholds, and a comprehensive ocular surface examination. The main outcome measures were correlations between corneal thresholds and signs and symptoms of dry eye and ocular pain. RESULTS: A total of 129 subjects participated in the study (mean age 64 ± 10 years). Mechanical detection and pain thresholds on the cornea correlated with age (Spearman's ρ = 0.26, 0.23, respectively; both P < 0.05), implying decreased corneal sensitivity with age. Dry eye symptom severity scores and Neuropathic Pain Symptom Inventory (modified for the eye) scores negatively correlated with corneal detection and pain thresholds (range, r = -0.13 to -0.27, P < 0.05 for values between -0.18 and -0.27), suggesting increased corneal sensitivity in those with more severe ocular complaints. Ocular signs, on the other hand, correlated poorly and nonsignificantly with mechanical detection and pain thresholds on the cornea. A multivariable linear regression model found that both posttraumatic stress disorder (PTSD) score (ß = 0.21, SE = 0.03) and corneal pain threshold (ß = -0.03, SE = 0.01) were significantly associated with self-reported evoked eye pain (pain to wind, light, temperature) and explained approximately 32% of measurement variability (R = 0.57). CONCLUSIONS: Mechanical detection and pain thresholds measured on the cornea are correlated with dry eye symptoms and ocular pain. This suggests hypersensitivity within the corneal somatosensory pathways in patients with greater dry eye and ocular pain complaints.

[Chemical composition features of vitreous in terminal glaucoma and hypertensive pain syndrome].

In patients with terminal glaucoma and hypertensive pain syndrome urea concentration in vitreous was 3,8-46,8 mmol/l and creatinine concentration was 0,036 - 0,126 mmol/l. Obtained values are comparable with those in blood serum and correlate with intensity of pain in damaged eye. Pain origin was found to be associated with elevation of urea concentration in vitreous compared with that in blood. It is proposed that urea accumulation in vitreous is one of significant factors of ocular pressure elevation in terminal glaucoma.

[Pathogenesis of hypertensive pain syndrome].

Comparative analysis of urea concentration in vitreous, vitreal fluid cavities and blood serum in patients with terminal painful glaucoma is performed based on laboratory data. Author proposes that pathogenesis of pain is related to "negative gradient of urea concentration", when urea concentration is higher in vitreous compared with blood serum. In the walls of ciliary processes where pain receptors are localized osmotic force causes tension provoking pain.