Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

González-González, Omar; Bech, Federico; Gallar, Juana; Merayo‐Lloves, Jesús; Belmonte, Carlos

doi:10.1167/iovs.16-20033

Cited by 75 publications

(88 citation statements)

References 82 publications

(153 reference statements)

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“…From previous studies in intact mice corneas, 33 we defined the fraction of the nerve terminals of the intact cornea responding only to mechanical force as mechano-nociceptors and those activated by heat and mechanical force as polymodal nociceptors. Finally, cold thermoreceptors, initially defined by their responsiveness to cooling, were subclassified by the value of their spontaneous firing at 348C and the temperature threshold required to increase their firing rate with a cooling ramp 33 as high-background ( ‡1.5 NTIÁs À1 ), low-threshold ( ‡30.58C) cold thermoreceptors (HB-LT), or low-background (<1.5 NTIÁs À1 ) high-threshold (<30.58C) cold thermoreceptors (LB-HT). Altogether, in the central cornea 54.1% of the terminals were identified as cold thermoreceptors, 26.7% as polymodal nociceptors, and 10% as mechano-nociceptors.…”

Section: Resultsmentioning

confidence: 99%

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Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy

Bech

González-González

Artime

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To define the characteristics and time course of the morphologic and functional changes experienced by corneal sensory nerves after photorefractive keratectomy (PRK).METHODS. Unilateral corneal excimer laser photoablation was performed in 54 anesthetized 3-to 6-month-old mice; 11 naïve animals served as control. Mice were killed 0, 3, 7, 15, and 30 days after PRK. Excised eyes were placed in a recording chamber superfused at 348C. Electrical nerve impulse activity of single sensory terminals was recorded with a micropipette applied onto the corneal surface. Spontaneous and stimulus-evoked (cold, heat, mechanical, and chemical stimuli) nerve terminal impulse (NTI) activity was analyzed. Corneas were fixed and stained with anti-b-Tubulin III antibody to measure nerve density and number of epithelial nerve penetration points of regenerating subbasal leashes.RESULTS. Nerve fibers and NTI activity were absent in the injured area between 0 and 7 days after PRK, when sparse regenerating nerve sprouts appear. On day 15, subbasal nerve density reached half the control value and abnormally responding cold-sensitive terminals were recorded inside the lesion. Thirty days after PRK, nerve density was almost restored, active cold thermoreceptors were abundant, and polymodal nociceptor activity first reappeared.CONCLUSIONS. Morphologic regeneration of subbasal corneal nerves started shortly after PRK ablation and was substantially completed 30 days later. Functional recovery appears faster in cold terminals than polymodal terminals, possibly reflecting an incomplete damage of the more extensively branched cold-sensitive axon terminals. Evolution of postsurgical discomfort sensations quality may be associated with the variable regeneration pattern of each fiber type.

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Section: Resultsmentioning

confidence: 99%

“…First, one half of the cornea was explored starting in the center and descending to the periphery; then, the eye was rotated and the opposite side of the cornea was explored. 33 After 90 minutes of recording attempts, the eye was fixed and prepared for morphologic studies.…”

Section: Experimental Protocolmentioning

confidence: 99%

Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy

Bech

González-González

Artime

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Corneal cold thermoreceptors are sensitive to menthol and virtually absent in the TRPM8-deficient mice (Parra et al, 2010). Depending on the subtype, they exhibit cooling thresholds around 32 or 28° and silence at 23 or 17°C, respectively (Gonzalez-Gonzalez et al, 2017). We first characterized a similar fiber type in skin-nerve preparations of 129S1/SvImJ mice (Zimmermann et al, 2011), albeit with a dynamic range that includes noxious temperatures.…”

Section: Resultsmentioning

confidence: 99%

Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse

Winter

Gruschwitz

Eger

et al. 2017

Front. Mol. Neurosci.

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Previous research identified TRPM8 and TRPA1 cold transducers with separate functions, one being functional in the non-noxious range and the second one being a nociceptive transducer. TRPM8-deficient mice present overt deficits in the detection of environmental cool, but not a lack of cold avoidance and TRPA1-deficient mice show clear deficits in some cold nocifensive assays. The extent of TRPA1's contribution to cold sensing in vivo is still unclear, because mice lacking both TRPM8 and TRPA1 (DKO) were described with unchanged cold avoidance from TRPM8−/− based on a two-temperature-choice assay and by c-fos measurement. The present study was designed to differentiate how much TRPM8 alone and combined TRPA1 and TRPM8 contribute to cold sensing. We analyzed behavior in the thermal ring track assay adjusted between 30 and 5°C and found a large reduction in cold avoidance of the double knockout mice as compared to the TRPM8-deficient mice. We also revisited skin-nerve recordings from saphenous-nerve skin preparations with regard to nociceptors and thermoreceptors. We compared the frequency and characteristics of the cold responses of TRPM8-expressing and TRPM8-negative C-fiber nociceptors in C57BL/6J mice with nociceptors of TRPM8-deficient and DKO mice and found that TRPM8 enables nociceptors to encode cold temperatures with higher firing rates and larger responses with sustained, static component. In TRPM8−/−, C-fiber cold nociceptors were markedly reduced and appeared further reduced in DKO. Nevertheless, the remaining cold responses in both knockout strains were similar in their characteristics and they were indifferent from the TRPM8-negative cold responses found in C57BL/6J mice. TRPM8 had a comparably essential role for encoding cold in thermoreceptors and lack of TRPM8 reduced response magnitude, peak and mean firing rates and the incidence of thermoreceptors. The encoding deficits were similar in the DKO strain. Our data illustrate that lack of TRPA1 in TRPM8-deficient mice results in a disproportionately large reduction in cold avoidance behavior and also affects the incidence of cold encoding fiber types. Presumably TRPA1 compensates for lack of TRPM8 to a certain extent and both channels cooperate to cover the entire cold temperature range, making cold-temperature encoding by TRPA1—although less powerful—synergistic to TRPM8.

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“…[60,61,93–95], thus ressembling the canonical cold thermoreceptors reported in other body tissues. This population of cold thermoreceptors has been named high background, low threshold (HB-LT) corneal cold thermoreceptors [96]. HB-LT cold thermoreceptors change their activity at different static temperatures and are much more strongly modulated by dynamic changes in temperature [28,61].…”

Section: Neurobiological Features In Normal/non Dry Eye Diseasementioning

confidence: 99%

TFOS DEWS II pain and sensation report

et al. 2017

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Pain associated to mechanical and chemical irritation of the eye surface is mediated by trigeminal ganglia mechano- and polymodal nociceptor neurons while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of Meibonian gland secretion or mucins release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.

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Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

Cited by 75 publications

References 82 publications

Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy

Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy

Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse

TFOS DEWS II pain and sensation report

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