Lacosamide diminishes dryness-induced hyperexcitability of corneal cold sensitive nerve terminals

Kovács, Illés; Dienes, Lóránt; Perényi, Kristóf; Quirce, Susana; Luna, Carolina; Mizerska, Kamila; Acosta, M. Carmen; Belmonte, Carlos; Gallar, Juana

doi:10.1016/j.ejphar.2016.05.044

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…This suggests that some degree of nerve damage is an important pathological consequence of DED. Nonetheless, in corneal cold neurons of teardeficient animals, cold-and menthol-evoked [Ca 2ϩ ] i responses and I TRPM8 were normal (Kovács et al, 2016a), whereas bigger sodium currents and decreased potassium currents were recorded. The apparent absence of a functional overexpression of TRPM8 in these DED cold neurons despite the morphological evidence of peripheral nerve damage suggests that in experimental DED corneas, enhanced ongoing firing of cold thermoreceptor terminals is due to dysregulation of voltage-gated sodium and potassium channels, rather than TRPM8.…”

Section: Discussionmentioning

confidence: 93%

Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage

et al. 2019

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The cornea is extensively innervated by trigeminal ganglion cold thermoreceptor neurons expressing TRPM8 (transient receptor potential cation channel subfamily M member 8). These neurons respond to cooling, hyperosmolarity and wetness of the corneal surface. Surgical injury of corneal nerve fibers alters tear production and often causes dry eye sensation. The contribution of TRPM8-expressing corneal cold-sensitive neurons (CCSNs) to these symptoms is unclear. Using extracellular recording of CCSNs nerve terminals combined with in vivo confocal tracking of reinnervation, Ca 2ϩ imaging and patch-clamp recordings of fluorescent retrogradely labeled corneal neurons in culture, we analyzed the functional modifications of CCSNs induced by peripheral axonal damage in male mice. After injury, the percentage of CCSNs, the cold-and menthol-evoked intracellular [Ca 2ϩ ] rises and the TRPM8 current density in CCSNs were larger than in sham animals, with no differences in the brake K ϩ current I KD. Active and passive membrane properties of CCSNs from both groups were alike and corresponded mainly to those of canonical low-and high-threshold cold thermoreceptor neurons. Ongoing firing activity and menthol sensitivity were higher in CCSN terminals of injured mice, an observation accounted for by mathematical modeling. These functional changes developed in parallel with a partial reinnervation of the cornea by TRPM8(ϩ) fibers and with an increase in basal tearing in injured animals compared with sham mice. Our results unveil key TRPM8-dependent functional changes in CCSNs in response to injury, suggesting that increased tearing rate and ocular dryness sensation derived from deep surgical ablation of corneal nerves are due to enhanced functional expression of TRPM8 channels in these injured trigeminal primary sensory neurons.

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Section: Discussionmentioning

confidence: 93%

Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage

et al. 2019

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“…In our experiments, a suction electrode was used to record the activity of an entire ciliary nerve, which provides a larger innervation of the corneal surface compared to an isolated corneal nerve fibre. Thus, this experimental configuration differs from that using an Ag‐AgCl electrode for monopolar recordings of single‐unit impulse activity in guinea pigs or cats (Acosta et al., , ; Gallar et al., ; Kovacs, Dienes, et al., 2016a; Marfurt et al., ). By recording multi‐unit activity, we observed a higher spontaneous firing frequency in mice than in single‐unit recordings performed in guinea pigs or cats (Acosta et al., , ; Gallar et al., ).…”

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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“…This translational research ultimately seeks to produce more meaningful, applicable results that directly benefit patients with DED. Accordingly, we have developed an experimental model of dry eye in guinea pigs through the removal of the main lacrimal gland, which leads to a long-term reduction in basal tearing [64,69]. The morphological changes of corneal nerves four weeks after removal of the lacrimal gland include a significantly reduction in the number of peripheral sub-basal leashes throughout the cornea, which each adopt a quite tortuous trajectory and cover shorter distances.…”

Section: Corneal Nerve Function Impairment In Dry Eye Disease (I Kovacs)mentioning

confidence: 99%

“…Lacosamide is an anti-epileptic drug that is also used to treat painful diabetic neuropathy and it acts through slow inactivation of voltage-gated sodium channels [72]. Topical application of Lacosamide to the guinea pig eye surface significantly limits the increase in spontaneous activity and the responsiveness to cold of corneal sensory nerves in tear-deficient animals four weeks after unilateral removal of the main lacrimal gland [69]. Hence, we speculated that Lacosamide might reduce the hyperexcitability of corneal cold receptors caused by prolonged ocular surface dryness in hyposecretory or evaporative DED.…”

Section: Corneal Nerve Function Impairment In Dry Eye Disease (I Kovacs)mentioning

confidence: 99%

Reflections on the Ocular Surface: Summary of the Presentations at the 4th Coronis Foundation Ophthalmic Symposium Debate: “A Multifactorial Approach to Ocular Surface Disorders” (August 31 2021)

Bron¹,

Doğru²,

Horwath‐Winter³

et al. 2022

Front. Biosci. (Landmark Ed)

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Lacosamide diminishes dryness-induced hyperexcitability of corneal cold sensitive nerve terminals

Cited by 9 publications

References 48 publications

Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage

Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage

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

Reflections on the Ocular Surface: Summary of the Presentations at the 4th Coronis Foundation Ophthalmic Symposium Debate: “A Multifactorial Approach to Ocular Surface Disorders” (August 31 2021)

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