Menthol Activation of Corneal Cool Cells Induces TRPM8-Mediated Lacrimation but Not Nociceptive Responses in Rodents

Robbins, Ashlee; Kurose, Masayuki; Winterson, Barbara J.; Meng, Ian D.

doi:10.1167/iovs.12-10025

Cited by 67 publications

(84 citation statements)

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“…In these studies, low concentrations of menthol produced an increase in sensitivity to cold stimuli and enhanced cold-evoked neuronal discharge from spinal cord dorsal horn neurons, whereas high concentrations caused a decrease in cold sensitivity and inhibited cold-evoked discharge from dorsal horn neurons. In the dry eye animal, the desensitization following 500 M menthol is similar to an effect previously described after 50 mM menthol in control animals (Robbins et al 2012). This effect is also reminiscent of the capsaicin-induced desensitization via TRPV1 in polymodal nociceptors (Koplas et al 1997;Mohapatra and Nau 2003).…”

Section: Discussionsupporting

confidence: 82%

“…Activation of TRPM8 channels has been proposed as a treatment for dry eye, offering potential benefits over current treatments that involve the repeated application of lubricating artificial tears (Hirata and Meng 2010;Parra et al 2010;Robbins et al 2012). Although the application of menthol under control conditions may increase tear secretions without producing unwanted side effects, our results suggest that this may not be the case in the dry eye condition.…”

Section: Discussionmentioning

confidence: 62%

“…Heat-evoked discharge was calculated by subtracting the average baseline activity from the average activity evoked during the stimulus. Menthol-evoked discharge was determined using the response magnitude (Rmag), which was calculated by subtracting the mean baseline activity plus 2SD from the activity evoked 0 -30 and 30 -120 s after drug application (Robbins et al 2012).…”

Section: Methodsmentioning

confidence: 99%

“…These corneal cool cells are also activated by menthol, an agonist to the transient receptor potential melastatin 8 (TRPM8) channel, and by hyperosmotic stimuli (Acosta et al 2001a;Gallar et al 1993;Hirata and Meng 2010;Madrid et al 2006). Corneal cool cells are involved in a reflex that promotes tear production in response to drying of the ocular surface (Parra et al 2010;Robbins et al 2012). Activation of this tearing reflex does not appear to be accompanied by irritation or pain, which has led to the suggestion that TRPM8 agonists may be useful for the treatment of dry eye (Hirata and Meng 2010;Parra et al 2010;Robbins et al 2012).…”

mentioning

confidence: 99%

“…Corneal cool cells are involved in a reflex that promotes tear production in response to drying of the ocular surface (Parra et al 2010;Robbins et al 2012). Activation of this tearing reflex does not appear to be accompanied by irritation or pain, which has led to the suggestion that TRPM8 agonists may be useful for the treatment of dry eye (Hirata and Meng 2010;Parra et al 2010;Robbins et al 2012).…”

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confidence: 99%

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Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Kurose

Meng

2013

Journal of Neurophysiology

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Kurose M, Meng ID. Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells. J Neurophysiol 110: 495-504, 2013. First published May 1, 2013 doi:10.1152/jn.00222.2013.-Dry eye syndrome is a painful condition caused by inadequate or altered tear film on the ocular surface. Primary afferent cool cells innervating the cornea regulate the ocular fluid status by increasing reflex tearing in response to evaporative cooling and hyperosmicity. It has been proposed that activation of corneal cool cells via a transient receptor potential melastatin 8 (TRPM8) channel agonist may represent a potential therapeutic intervention to treat dry eye. This study examined the effect of dry eye on the response properties of corneal cool cells and the ability of the TRPM8 agonist menthol to modify these properties. A unilateral dry eye condition was created in rats by removing the left lacrimal gland. Lacrimal gland removal reduced tears in the dry eye to 35% compared with the contralateral eye and increased the number of spontaneous blinks in the dry eye by over 300%. Extracellular single-unit recordings were performed 8 -10 wk following surgery in the trigeminal ganglion of dry eye animals and age-matched controls. Responses of corneal cool cells to cooling were examined after the application of menthol (10 M-1.0 mM) to the ocular surface. The peak frequency of discharge to cooling was higher and the cooling threshold was warmer in dry eye animals compared with controls. The dry condition also altered the neuronal sensitivity to menthol, causing desensitization to cold-evoked responses at concentrations that produced facilitation in control animals. The mentholinduced desensitization of corneal cool cells would likely result in reduced tearing, a deleterious effect in individuals with dry eye.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 62%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Kurose

Meng

2013

Journal of Neurophysiology

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Select noxious stimuli induce changes on corneal nerve morphology

Hegarty

Hermes

Yang

et al. 2017

J of Comparative Neurology

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The surface of the cornea contains the highest density of nociceptive nerves of any tissue in the body. These nerves are responsive to a variety of modalities of noxious stimuli and can signal pain even when activated by low threshold stimulation. Injury of corneal nerves can lead to altered nerve morphology, including neuropathic changes which can be associated with chronic pain. Emerging technologies that allow imaging of corneal nerves in vivo are spawning questions regarding the relationship between corneal nerve density, morphology, and function. We tested whether noxious stimulation of the corneal surface can alter nerve morphology and neurochemistry. We used concentrations of menthol, capsaicin, and hypertonic saline that evoked comparable levels of nocifensive eye wipe behaviors when applied to the ocular surface of an awake rat. Animals were sacrificed and corneal nerves were examined using immunocytochemistry and three-dimensional volumetric analyses. We found that menthol and capsaicin both caused a significant reduction in corneal nerve density as detected with β-tubulin immunoreactivity 2 hr after stimulation. Hypertonic saline did not reduce nerve density, but did cause qualitative changes in nerves including enlarged varicosities that were also seen following capsaicin and menthol stimulation. All three types of noxious stimuli caused a depletion of CGRP from corneal nerves, indicating that all modalities of noxious stimuli evoked peptide release. Our findings suggest that studies aimed at understanding the relationship between corneal nerve morphology and chronic disease may also need to consider the effects of acute stimulation on corneal nerve morphology.

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Morphological and functional changes in TRPM8‐expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice

Alcalde

Íñigo-Portugués

González-González

et al. 2018

J of Comparative Neurology

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Morphological and functional alterations of peripheral somatosensory neurons during the aging process lead to a decline of somatosensory perception. Here, we analyze the changes occurring with aging in trigeminal ganglion (TG), TRPM8-expressing cold thermoreceptor neurons innervating the mouse cornea, which participate in the regulation of basal tearing and blinking and have been implicated in the pathogenesis of dry eye disease (DED). TG cell bodies and axonal branches were examined in a mouse line (TRPM8 -EYFP) expressing a fluorescent reporter. In 3 months old animals, about 50% of TG cold thermoreceptor neurons were intensely fluorescent, likely providing strongly fluorescent axons and complex corneal nerve terminals with ongoing activity at 34°C and low-threshold, robust responses to cooling. The remaining TRPM8 corneal axons were weakly fluorescent with nonbeaded axons, sparsely ramified nerve terminals, and exhibited a low-firing rate at 34°C, responding moderately to cooling pulses as do weakly fluorescent TG neurons. In aged (24 months) mice, the number of weakly fluorescent TG neurons was strikingly high while the morphology of TRPM8 corneal axons changed drastically; 89% were weakly fluorescent, unbranched, and often ending in the basal epithelium. Functionally, 72.5% of aged cold terminals responded as those of young animals, but 27.5% exhibited very low-background activity and abnormal responsiveness to cooling pulses. These morpho-functional changes develop in parallel with an enhancement of tear's basal flow and osmolarity, suggesting that the aberrant sensory inflow to the brain from impaired peripheral cold thermoreceptors contributes to age-induced abnormal tearing and to the high incidence of DED in elderly people.

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Menthol Activation of Corneal Cool Cells Induces TRPM8-Mediated Lacrimation but Not Nociceptive Responses in Rodents

Cited by 67 publications

References 64 publications

Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells

Select noxious stimuli induce changes on corneal nerve morphology

Morphological and functional changes in TRPM8‐expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice

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