Ocular surface information seen from the somatosensory thalamus and cortex.

Ocular Surface (OS) somatosensory innervation detects external stimuli producing perceptions, such as pain or dryness, the most relevant symptoms in many OS pathologies. Nevertheless, little is known about the central nervous system circuits involved in these perceptions, and how they integrate multimodal inputs in general. Here, we aim to describe the thalamic and cortical activity in response to OS stimulation of different modalities. Electrophysiological extracellular recordings in anaesthetized rats were used to record neural activity, while saline drops at different temperatures were applied to stimulate the OS. Neurons were recorded in the ophthalmic branch of the trigeminal ganglion (TG, 49 units), the thalamic VPM-POm nuclei representing the face (Th, 69 units) and the primary somatosensory cortex (S1, 101 units). The precise locations for Th and S1 neurons receiving OS information are reported here for the first time. Interestingly, all recorded nuclei encode modality both at the single neuron and population levels, with noxious stimulation producing a qualitatively different activity profile from other modalities. Moreover, neurons responding to new combinations of stimulus modalities not present in the peripheral TG subsequently appear in Th and S1, being organized in space through the formation of clusters. Besides, neurons that present higher multimodality display higher spontaneous activity. These results constitute the first anatomical and functional characterization of the thalamocortical representation of the OS. Furthermore, they provide insight into how information from different modalities gets integrated from the peripheral nervous system into the complex cortical networks of the brain. KEY POINTS: Anatomical location of thalamic and cortical ocular surface representation. Thalamic and cortical neuronal responses to multimodal stimulation of the ocular surface. Increasing functional complexity along trigeminal neuroaxis. Proposal of a new perspective on how peripheral activity shapes central nervous system function.

Functional Changes of the Ocular Surface Sensory Nerves Due to Contact Lens Use in Young Symptomatic and Asymptomatic Users.

Purpose: The purpose of this study was to analyze the differences in corneal sensory nerve functionality in young asymptomatic (CL-A) and symptomatic (CL-S) contact lens (CL) users. Methods: CL wearers (23.8 ± 1.0 years, n = 31) were classified as CL-S with an Ocular Surface Disease Index (OSDI) ≥ 13 (n = 14) or CL-A. Users of eye glasses (EG; 24.5 ± 0.8 years, n = 29) with OSDI < 13 participated as controls. The sensations evoked by mechanical, chemical (gas esthesiometer), and cold (4°C saline drops) stimuli were measured using the Visual Analogue Scales (VASs). Moreover, tear volume, tear break up time (TBUT), blinking frequency (BF), and ocular surface temperature (OST; IR thermography) were also measured. Results: Mechanical and chemical stimuli produced similar scores in the CL-A and EG participants, although the CL-A subjects referred to stronger irritation (p < 0.05). Likewise, the VAS intensity in response to cold stimuli did not differ between CL-A and EG subjects, while the ability to detect cold was significantly worse in CL-S users (p < 0.05). CL-A users had a similar tear volume, a higher BF (p < 0.01) and shorter TBUT (p < 0.001) to EG wearers, and blinking and TBUT were also altered significantly in CL-S users (p < 0.01). Interestingly, the OST was significantly lower in CL-A users (p < 0.05) than in EG wearers, but not in CL-S users. Conclusions: Using CLs modifies corneal sensitivity, blinking and tearing in young volunteers. Even if they have yet to develop clinical signs of inflammation, they display changes in corneal sensitivity consistent with the sensitization of corneal nociceptors and the inhibition cold thermoreceptors, phenomena that occur under inflammatory conditions. The differences in corneal sensitivity and OST between CL-A and CL-S users could reflect the extent of nerve damage and inflammation at the ocular surface.

The Contribution of TRPA1 to Corneal Thermosensitivity and Blink Regulation in Young and Aged Mice.

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors' activity was recorded extracellularly in young (5-month-old) and aged (18-month-old) C57BL/6WT (WT) and TRPA1-/- knockout (TRPA1-KO) mice at basal temperature (34 °C) and during cooling (15 °C) and heating (45 °C) ramps. The blink response to cold and heat stimulation of the ocular surface and the basal tearing rate were also measured in young animals using orbicularis oculi muscle electromyography (OOemg) and phenol red threads, respectively. The background activity at 34 °C and the cooling- and heating-evoked responses of the cold thermoreceptors were similar in WT and TRPA1-KO animals, no matter the age. Similar to the aged WT mice, in the young and aged TRPA1-KO mice, most of the cold thermoreceptors presented low frequency background activity, a low cooling threshold, and a sluggish response to heating. The amplitude and duration of the OOemg signals correlated with the magnitude of the induced thermal change in the WT but not in the TRPA1-KO mice. The basal tearing was similar in the TRPA1-KO and WT mice. The electrophysiological data suggest that the TRPA1-dependent nerve activity, which declines with age, contributes to detecting the warming of the ocular surface and also to integrating the thermally-evoked reflex blink.

Cyclosporine A Decreases Dryness-Induced Hyperexcitability of Corneal Cold-Sensitive Nerve Terminals.

Cyclosporine A (CsA) is used for the treatment of dry eye (DE) with good clinical results, improving tear secretion and decreasing subjective symptoms. These effects are attributed to the improved tear film dynamics, but there are no data on the effect of CsA on the abnormal sensory nerve activity characteristic in DE. Our purpose was to evaluate the CsA effect on the enhanced activity of corneal cold thermoreceptors in a tear-deficient DE animal model using in vitro extracellular recording of cold thermoreceptors nerve terminal impulses (NTIs) before and in the presence of CsA. NTI shape was also analyzed. Blinking frequency and tearing rate were also measured in awake animals before and after topical CsA. CsA increased the tearing and blinking of treated animals. CsA significantly decreased the peak response to cold of cold thermoreceptors. Neither their spontaneous NTIs discharge rate nor their cooling threshold were modified. CsA also seemed to reverse some of the changes in NTI shape induced by tear deficiency. These data suggest that, at least in part, the beneficial clinical effects of CsA in DE can be attributed to a direct effect on sensory nerve endings, although the precise mechanisms underlying this effect need further studies to be fully clarified.

Effects of physical activity/exercise on tear film characteristics and dry eye associated symptoms: A literature review.

PURPOSE: To conduct a review of the literature in order to identify the potential association between physical activity or exercise and the objective signs and/or subjective symptoms of dry-eye disease. METHODS: A review of PubMed and Web of Science databases was performed, according to the PRISMA guidelines. The papers included in the review addressed the relationship of physical activity or exercise with dry-eye associated signs (changes in tear volume, osmolarity or biochemical composition) and/or subjective symptoms. RESULTS: A total of 16 papers were included. In eight, the changes in tear film volume, osmolarity and/or biochemical composition were studied after a single, acute bout of aerobic exercise. In another eight, changes in dry-eye associated symptoms were studied in relation to the habitual practice of physical activity or to prescribed exercise programmes. Acute responses of the tear film to exercise included: a) an increase of tear volume, without an increase of the tear break-up time; b) a trend to increase tear osmolarity, although within its physiological range; and c) a reduced concentration of several cytokines, and other molecular markers of inflammation or oxidative stress. Long-term exposure to physical activity or exercise programmes was associated with relief of dry-eye associated symptoms and a trend to increased tear break-up time. CONCLUSIONS: Despite a high heterogeneity in the studied population, study designs and methods, the current body of evidence suggests a potential role for physical activity as a modulatory stimulus for the proper functioning of the tear film and/or the relief of dry-eye symptoms.

Maximal tear secretion evoked by controlled stimulation of corneal sensory nerves in healthy individuals and dry eye subjects.

PURPOSE: To measure, the tear flow changes evoked in healthy subjects and dry eye disease (DED) patients by controlled sensory stimulation of the eye surface with i-Onion™, a new stimulation device. METHODS: Sensory corneal nerves were stimulated with an instrument (i-Onion™) that ejects puffs of CO2 gas (99.9%) at 200 ml·min-1 for 3s, delivered 5 mm from the cornea. Using Schirmer test strips, tear volumes were measured over 3 min in the cornea of one eye before (basal tear volume -BTV) and in the other eye after stimulation of the sensory nerves with CO2 (stimulated tear volume -STV). These measurements were obtained from a control group of adults of either sex (17 students aged 20-30 and 29 subjects without signs of dry eye aged 25-61), a cohort of DED patients (aged 34-75) that included 12 asymptomatic, suspected DED subjects (Schirmer <7 mm and/or TBUT <10s), and 30 Sjögren's syndrome (SS) patients. RESULTS: CO2 stimulation significantly increased the tear volume (BTV = 14.6 ± 1.0 mm, STV = 19.0 ± 1.1 mm: n = 46) in 78% of control subjects, reflecting a mean tear reserve volume (TRV = STV-BTV) of 4.4 ± 0.8 mm. Individual differences were wide, and while no increase in reflex tearing was evoked in 30% of subjects with a BTV >10 mm, the remaining 70% responded vigorously to stimulation, even those with a BTV >18 mm. Asymptomatic DED subjects displayed weaker responses to CO2 stimulation, with lower STVs. Both the BTV and STV of SS patients were low, significantly below those of the healthy controls. CONCLUSIONS: Measuring the rise in reflex tearing volume evoked by controlled corneal stimulation provides objective information about the tear glands' secretory capacity in health and disease.

Thoracoscopic segmentectomy versus lobectomy: A propensity score-matched analysis.

Objectives: The aim of this study is to compare the postoperative complications, perioperative course, and survival among patients from the multicentric Spanish Video-assisted Thoracic Surgery Group database who received video-assisted thoracic surgery lobectomy or video-assisted thoracic surgery anatomic segmentectomy. Methods: From December 2016 to March 2018, a total of 2250 patients were collected from 33 centers. Overall analysis (video-assisted thoracic surgery lobectomy = 2070; video-assisted thoracic surgery anatomic segmentectomy = 180) and propensity score-matched adjusted analysis (video-assisted thoracic surgery lobectomy = 97; video-assisted thoracic surgery anatomic segmentectomy = 97) were performed to compare postoperative results. Kaplan-Meier and competing risks method were used to compare survival. Results: In the overall analysis, video-assisted thoracic surgery anatomic segmentectomy showed a lower incidence of respiratory complications (relative risk, 0.56; confidence interval, 0.37-0.83; P = .002), lower postoperative prolonged air leak (relative risk, 0.42; 95% confidence interval, 0.23-0.78; P = .003), and shorter median postoperative stay (4.8 vs 6.2 days; P = .004) than video-assisted thoracic surgery lobectomy. After propensity score-matched analysis, prolonged air leak remained significantly lower in video-assisted thoracic surgery anatomic segmentectomy (relative risk, 0.33; 95% confidence interval, 0.12-0.89; P = .02). Kaplan-Meier and competing risk curves showed no differences during the 3-year follow-up (median follow-up in months: 24.4; interquartile range, 20.8-28.3) in terms of overall survival (hazard ratio, 0.73; 95% confidence interval, 0.45-1.7; P = .2), tumor progression-related mortality (subdistribution hazard ratio, 0.41; 95% confidence interval, 0.11-1.57; P = .2), and disease-free survival (subdistribution hazard ratio, 0.73; 95% confidence interval, 0.35-1.51; P = .4) between groups. Conclusions: Video-assisted thoracic surgery segmentectomy showed results similar to lobectomy in terms of postoperative outcomes and midterm survival. In addition, a lower incidence of prolonged air leak was found in patients who underwent video-assisted thoracic surgery anatomic segmentectomy.

OSDI Questions on Daily Life Activities Allow to Detect Subclinical Dry Eye in Young Contact Lens Users.

Dry eye disease (DED) is difficult to detect in young contact lens (CL) wearers, who usually have no signs, mild symptoms and an ocular surface disease index (OSDI) below the DED diagnosis values (OSDI ≥ 13). We investigate if some of the 12 OSDI questions (OSDI A­ocular symptoms; OSDI B­vision-related functionality; OSDI C­environmental triggers) contribute the most to classify young CL as symptomatic. TBUT and tear volume are also measured. Age, gender and refraction error-matched eye glasses (EG) wearers participated as the control. CL and EG data were compared with t-test and z-test. Confusion matrices and logistic correlation analyses were performed to define the contribution of each OSDI question to classify symptomatic subjects. OSDI classified symptomatic CL better than the tear volume or TBUT values. In CL, only OSDI B and C values were significantly higher in symptomatic vs. asymptomatic subjects (p < 0.001), while values of all twelve OSDI questions were significantly higher in symptomatic vs. asymptomatic EG (p < 0.05−0.001). All OSDI questions contribute equally to identify symptomatic EG, while only OSDI B questions on daily life visual functions are significant to classify symptomatic CL wearers at risk to develop DED or at a subclinical stage. CL wearers scoring ≥ 2 on the OSDI B questions should be considered for preventive treatments, even if their clinical sings are scarce or absent.

An Experimental Model of Neuro-Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells.

The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye.

Epithelial and sensory mechanisms of nasal hyperreactivity.

"Nasal hyperreactivity" is a key feature in various phenotypes of upper airway diseases, whereby reactions of the nasal epithelium to diverse chemical and physical stimuli are exacerbated. In this review, we illustrate how nasal hyperreactivity can result from at least three types of mechanisms: (1) impaired barrier function, (2) hypersensitivity to external and endogenous stimuli, and (3) potentiation of efferent systems. We describe the known molecular basis of hyperreactivity related to the functional impairment of epithelial cells and somatosensory innervation, and indicate that the thermal, chemical, and mechanical sensors determining hyperreactivity in humans remain to be identified. We delineate research directions that may provide new insights into nasal hyperreactivity associated with rhinitis/rhinosinusitis pathophysiology and therapeutics. The elucidation of the molecular mechanisms underlying nasal hyperreactivity is essential for the treatment of rhinitis according to the precepts of precision medicine.

A genetic compensatory mechanism regulated by Jun and Mef2d modulates the expression of distinct class IIa Hdacs to ensure peripheral nerve myelination and repair.

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5, and 7 but not Hdac9. Here, we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4, 5, and 7 are simultaneously removed, the myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.

Small fiber neuropathy in the cornea of Covid-19 patients associated with the generation of ocular surface disease.

PURPOSE: To describe the association between Sars-CoV-2 infection and small fiber neuropathy in the cornea identified by in vivo corneal confocal microscopy. METHODS: Twenty-three patients who had overcome COVID-19 were recruited to this observational retrospective study. Forty-six uninfected volunteers were also recruited and studied as a control group. All subjects were examined under in vivo confocal microscopy to obtain images of corneal subbasal nerve fibers in order to study the presence of neuroma-like structures, axonal beadings and dendritic cells. The Ocular Surface Disease Index (OSDI) questionnaire and Schirmer tear test were used as indicators of Dry Eye Disease (DED) and ocular surface pathology. RESULTS: Twenty-one patients (91.31%) presented alterations of the corneal subbasal plexus and corneal tissue consistent with small fiber neuropathy. Images from healthy subjects did not indicate significant nerve fiber or corneal tissue damage. Eight patients reported increased sensations of ocular dryness after COVID-19 infection and had positive DED indicators. Beaded axons were found in 82.60% of cases, mainly in patients reporting ocular irritation symptoms. Neuroma-like images were found in 65.22% patients, more frequently in those with OSDI scores >13. Dendritic cells were found in 69.56% of patients and were more frequent in younger asymptomatic patients. The presence of morphological alterations in patients up to 10 months after recovering from Sars-CoV-2 infection points to the chronic nature of the neuropathy. CONCLUSIONS: Sars-CoV-2 infection may be inducing small fiber neuropathy in the ocular surface, sharing symptomatology and morphological landmarks with DED and diabetic neuropathy.

Membrane potential instabilities in sensory neurons: mechanisms and pathophysiological relevance.

ABSTRACT: Peripheral sensory neurons transduce physicochemical stimuli affecting somatic tissues into the firing of action potentials that are conveyed to the central nervous system. This results in conscious perception, adaptation, and survival, but alterations of the firing patterns can result in pain and hypersensitivity conditions. Thus, understanding the molecular mechanisms underlying action potential firing in peripheral sensory neurons is essential in sensory biology and pathophysiology. Over the past 30 years, it has been consistently reported that these cells can display membrane potential instabilities (MPIs), in the form of subthreshold membrane potential oscillations or depolarizing spontaneous fluctuations. However, research on this subject remains sparse, without a clear conductive thread to be followed. To address this, we here provide a synthesis of the description, molecular bases, mathematical models, physiological roles, and pathophysiological implications of MPIs in peripheral sensory neurons. Membrane potential instabilities have been reported in trigeminal, dorsal root, and Mes-V ganglia, where they are believed to support repetitive firing. They are proposed to have roles also in intercellular communication, ectopic firing, and responses to tonic and slow natural stimuli. We highlight how MPIs are of great interest for the study of sensory transduction physiology and how they may represent therapeutic targets for many pathological conditions, such as acute and chronic pain, itch, and altered sensory perceptions. We identify future research directions, including the elucidation of the underlying molecular determinants and modulation mechanisms, their relation to the encoding of natural stimuli and their implication in pain and hypersensitivity conditions.

Unilateral Corneal Insult Also Alters Sensory Nerve Activity in the Contralateral Eye.

After the unilateral inflammation or nerve lesion of the ocular surface, the ipsilateral corneal sensory nerve activity is activated and sensitized, evoking ocular discomfort, irritation, and pain referred to the affected eye. Nonetheless, some patients with unilateral ocular inflammation, infection, or surgery also reported discomfort and pain in the contralateral eye. We explored the possibility that such altered sensations in the non-affected eye are due to the changes in their corneal sensory nerve activity in the contralateral, not directly affected eye. To test that hypothesis, we recorded the impulse activity of the corneal mechano- and polymodal nociceptor and cold thermoreceptor nerve terminals in both eyes of guinea pigs, subjected unilaterally to three different experimental conditions (UV-induced photokeratitis, microkeratome corneal surgery, and chronic tear deficiency caused by removal of the main lacrimal gland), and in eyes of naïve animals ex vivo. Overall, after unilateral eye damage, the corneal sensory nerve activity appeared to be also altered in the contralateral eye. Compared with the naïve guinea pigs, animals with unilateral UV-induced mild corneal inflammation, showed on both eyes an inhibition of the spontaneous and stimulus-evoked activity of cold thermoreceptors, and increased activity in nociceptors affecting both the ipsilateral and the contralateral eye. Unilateral microkeratome surgery affected the activity of nociceptors mostly, inducing sensitization in both eyes. The removal of the main lacrimal gland reduced tear volume and increased the cold thermoreceptor activity in both eyes. This is the first direct demonstration that unilateral corneal nerve lesion, especially ocular surface inflammation, functionally affects the activity of the different types of corneal sensory nerves in both the ipsilateral and contralateral eyes. The mechanisms underlying the contralateral affectation of sensory nerves remain to be determined, although available data support the involvement of neuroimmune interactions. The parallel alteration of nerve activity in contralateral eyes has two main implications: a) in the experimental design of both preclinical and clinical studies, where the contralateral eyes cannot be considered as a control; and, b) in the clinical practice, where clinicians must consider the convenience of treating both eyes of patients with unilateral ocular conditions to avoid pain and secondary undesirable effects in the fellow eye.

Deciphering the Action of Perfluorohexyloctane Eye Drops to Reduce Ocular Discomfort and Pain.

Perfluorohexyloctane (F6H8) eyedrops have been recently introduced in Europe as a product to treat dry eye disease, based on its ability to reduce tear film instability in Meibomian gland dysfunction and evaporative dry eye disease, although its mechanism of action is still unknown. In the present pilot study, we evaluated the effects of the ocular instillation of a single drop of commercial F6H8 eyedrops in 20 healthy humans (9 women/11 men), measuring: (a) Corneal surface temperature (CST) from infrared video images; (b) tear volume using phenol red threads; (c) blinking frequency; and (d) ocular surface sensations (cold, dryness, pricking, foreign body, burning, itching, gritty, eye fatigue, watering eyes, and light-evoked discomfort sensations; scored using 10 cm Visual Analog Scales), before and 5-60 min after F6H8 or saline treatment. CST decreased and tearing and blinking frequency increased significantly after F6H8 but not after saline solution. When applied unilaterally, CST decreased only in the F6H8-treated eye. No sensations were evoked after F6H8 or saline. The corneal surface temperature reduction produced by topical F6H8 does not evoke conscious ocular sensations but is sufficient to increase the activity of corneal cold thermoreceptors, leading to an increased reflex lacrimation and blinking that may relieve dry eye condition thus reducing ocular discomfort and pain.

Acute Increase in Blood αCGRP at Maximal Exercise and Its Association to Cardiorespiratory Fitness, Carbohydrate Oxidation and Work Performed: An Exploratory Study in Young Men.

This study aimed to explore if the acute variations in plasma concentration of α-calcitonin gene-related peptide (αCGRP) induced by a single maximal exercise bout may be associated to cardiorespiratory fitness and carbohydrate oxidation in humans. Twelve young adult Caucasian men (24.3 ± 0.9 years-old; 179.2 ± 1.9 cm of height; 23.9 ± 0.6 kg·m-2 body mass index) performed a graded exercise test. A venous catheter was placed before testing, and blood samples were taken at baseline, maximal effort and recovery. αCGRP was measured in plasma using a commercial double-sandwich enzyme-linked-immunoassay. A two-way repeated measurements ANOVA was used to compare the values obtained at baseline, maximal effort and recovery. In the whole sample, αCGRP increased at maximal effort and its concentration correlated directly, albeit non-significantly, with the muscle mass normalised VO2, VCO2, carbohydrate oxidation and relative power. Two thirds of the participants showed an increase in αCGRP concentration at maximal effort. Post hoc analysis showed that in these individuals, the muscle mass normalised VO2, VCO2, carbohydrate oxidation rate and relative power were higher than in the participants lacking this molecular response. Therefore, our data suggest that (a) a majority of young men respond to exercise with an increase in blood αCGRP concentration; and (b) individuals exhibiting this response also show a higher cardiorespiratory fitness, carbohydrate oxidation and work performed. These findings suggest that this neuropeptide could act as an exerkine with potential effects on physical performance.

Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal.

Free nerve endings are key structures in sensory transduction of noxious stimuli. In spite of this, little is known about their functional organization. Transient receptor potential (TRP) channels have emerged as key molecular identities in the sensory transduction of pain-producing stimuli, yet the vast majority of our knowledge about sensory TRP channel function is limited to data obtained from in vitro models which do not necessarily reflect physiological conditions. In recent years, the development of novel optical methods such as genetically encoded calcium indicators and photo-modulation of ion channel activity by pharmacological tools has provided an invaluable opportunity to directly assess nociceptive TRP channel function at the nerve terminal.

Sodium Channel Blockers Modulate Abnormal Activity of Regenerating Nociceptive Corneal Nerves After Surgical Lesion.

Purpose: To test the effect of different sodium channel blockers on the electrical activity of corneal nociceptors in intact and surgically injured corneas. Methods: In anesthetized guinea pigs, a 4-mm diameter corneal flap was performed in one eye at a midstromal depth using a custom-made microkeratome. At different times after surgery (3 hours to 15 days), the electrical activity of corneal nociceptor fibers was recorded from ciliary nerve filaments in the superfused eye in vitro. Mechanical threshold was measured using calibrated von Frey hairs; chemical stimulation was performed applying 30-second CO2 gas pulses. The characteristics of the spontaneous and stimulus-evoked activity of corneal nociceptors recorded from intact and lesioned corneas, before and after treatment with the sodium channel blockers lidocaine, carbamazepine, and amitriptyline, were compared. Results: No spontaneous or stimulus-evoked impulse activity was detected inside the flap at any of the studied time points. However, both were recorded from mechanonociceptor and polymodal nociceptors fibers in the surrounding corneal tissue, being significantly higher (sensitization) 24 to 48 hours after surgery. In these fibers, none of the tested drugs affected mechanical threshold, but they significantly reduced the CO2 response of polymodal nociceptors of intact and injured corneas. Likewise, they diminished significantly the transient increase in spontaneous and stimulus-evoked activity of sensitized polymodal nociceptors. Conclusions: Na+ channel blockers decrease the excitability of intact and sensitized corneal nociceptor fibers, thus acting as potential tools to attenuate their abnormal activity, which underlies the spontaneous pain, hyperalgesia, and allodynia often accompanying surgical corneal lesions, as occurs after photorefractive surgery.

Topical treatment with a mu opioid receptor agonist alleviates corneal allodynia and corneal nerve sensitization in mice.

Corneal pain is considered to be a core symptom of ocular surface disruption and inflammation. The management of this debilitating condition is still a therapeutic challenge. Recent evidence supports a role of the opioid system in the management of corneal nociception. However, the functional involvement of the mu opioid receptor (MOR) underlying this analgesic effect is not known. We first investigated the expression of the MOR in corneal nerve fibers and trigeminal ganglion (TG) neurons in control mice and a mouse model of corneal inflammatory pain. We then evaluated the anti-nociceptive and electrophysiological effects of DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol] enkephalin), a MOR-selective ligand. MOR immunoreactivity was detected in corneal nerve fibers and primary afferent neurons of the ophthalmic branch of the TG of naive mice. MOR expression was significantly higher in both structures under conditions of inflammatory corneal pain. Topical ocular administration of DAMGO strongly reduced both the mechanical (von Frey) and chemical (capsaicin) corneal hypersensitivity associated with inflammatory ocular pain. Repeated instillations of DAMGO also markedly reversed the elevated spontaneous activity of the ciliary nerve and responsiveness of corneal polymodal nociceptors that were observed in mice with corneal pain. Finally, these DAMGO-induced behavioral and electrophysiological responses were totally blunted by the topical application of naloxone methiodide, an opioid receptor antagonist. Overall, these results provide evidence that topical pharmacological MOR activation may constitute a therapeutic target for the treatment of corneal pain and improve corneal nerve function to alleviate chronic pain.