Dry eye sensitizes cool cells to capsaicin-induced changes in activity via TRPV1

Abstract

Corneal cool cells are sensitive to the ocular fluid status of the corneal surface and may be responsible for the regulation of basal tear production. Previously, we have shown that dry eye, induced by lacrimal gland excision (LGE) in rats, sensitized corneal cool cells to the transient receptor potential melastatin 8 (TRPM8) agonist menthol and to cool stimulation. In the present study, we examined the effect of dry eye on the sensitivity of cool cells to the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin. Single-unit recordings in the trigeminal ganglion were performed 7–10 days after LGE. At a concentration of 0.3 μM, capsaicin did not affect ongoing or cool-evoked activity in control animals yet facilitated ongoing activity and suppressed cool-evoked activity in LGE animals. At higher concentrations (3 μM), capsaicin continued to facilitate ongoing activity in LGE animals but suppressed ongoing activity in control animals. Higher concentrations of capsaicin also suppressed cool-evoked activity in both groups of animals, with an overall greater effect in LGE animals. In addition to altering cool-evoked activity, capsaicin enhanced the sensitivity of cool cells to heat in LGE animals. Capsaicin-induced changes were prevented by the application of the TRPV1 antagonist capsazepine. With the use of fluorescent in situ hybridization, TRPV1 and TRPM8 expression was examined in retrograde tracer-identified corneal neurons. The coexpression of TRPV1 and TRPM8 in corneal neurons was significantly greater in LGE-treated animals when compared with sham controls. These results indicate that LGE-induced dry eye increases TRPV1-mediated responses in corneal cool cells at least in part through the increased expression of TRPV1. NEW & NOTEWORTHY Corneal cool cells are known to detect drying of the ocular surface. Our study is the first to report that dry eye induced alterations in cool cell response properties, including the increased responsiveness to noxious heat and activation by capsaicin. Along with the changes in cell response properties, it is possible these neurons also function differently in dry eye, relaying information related to the perception of ocular irritation in addition to regulating tearing and blinking.

Morphological and Functional Changes of Corneal Nerves and Their Contribution to Peripheral and Central Sensory Abnormalities

“…In a moderate dry eye experimental model obtained after unilateral extraorbital lacrimal gland excision, Kurose et al demonstrated by a single unit extracellular recording of trigeminal neurons (8-10 weeks after the surgery) that dry eye sensitized corneal cool cells to the TRPM8 agonist menthol and to cool stimulation (Kurose and Meng, 2013). In the same experimental model, Hatta et al showed that dry eye increased responsiveness to noxious heat and activation by capsaicin through TRPV1 (Hatta et al, 2019) (Figure 3). Pina et al further demonstrated, in a mouse model of corneal injury, changes in cold sensitivity of corneal neurons in the TG through an enhanced functional expression of TRPM8 channels, suggesting that the increase in ocular dryness sensation and basal tearing rate observed after refractive surgery could be related to a disturbance in the TRPM8 responsiveness of cold sensory neurons (Kovacs et al, 2016b;Pina et al, 2019) (Figure 3).…”

“…Anatomical studies using retrograde-labeled corneal neuron experiments have found a higher expression of TRPV1 in TRPM8 + cold-sensing corneal neurons in the TG in a model of DED, suggesting an enhanced responsiveness of TRPM8 + cells and leading to a cold allodynia (Hatta et al, 2019 ; Li et al, 2019 ). Moreover, single cell RT-PCR indicated that all TRPM8 + /TRPV1+neurons express substance P (Tac1), while fewer TRPM8 + /TRPV1- neurons express Tac1.…”

Lacrimal gland excision in male and female mice causes ocular pain and anxiety-like behaviors

“…Several of these studies have examined several time points, beginning one week after excision and extending out to 8 weeks. Lacrimal gland excision-induced sensitization of corneal polymodal nociceptors and cold cells occurred within one week after excision and persisted for at least 4 weeks 16 – 18 . In the present study, the 2-week time point was chosen because of the significant differences noted between female and male mice in corneal inflammation 10 .…”

“…Corneal cold cells function to sense changes in ambient temperature and regulate basal tearing and blinking accordingly, without evoking nociceptive responses 54 , 55 . In tear deficient animals, corneal cold cells become sensitized to cooling 17 , 18 , 56 and have been proposed to be responsible, at least in part, for the irritation or pain caused by dry eye 16 . The TRPM8 agonist menthol (200 µM) has been shown to increase OOemg activity to a similar degree in both control and LGE rats 15 , whereas 100 µM menthol had no effect in either group.…”

“…Lacrimal gland excision (LGE) has been demonstrated to sensitize corneal polymodal nociceptive neurons to the TRPV1 agonist capsaicin and low pH induced by CO 2 , as well as sensitize corneal cold cells to the TRPM8 agonist menthol 11 , 15 – 17 . Furthermore, LGE-induced plasticity in corneal afferents includes an increase in co-expression of TRPM8 and TRPV1, which is matched by a greater proportion of cold responsive corneal afferents that are activated by noxious heat after LGE 18 .…”