Cold-Sensitive Corneal Afferents Respond to a Variety of Ocular Stimuli Central to Tear Production: Implications for Dry Eye Disease

Hirata, Harumitsu; Meng, Ian D.

doi:10.1167/iovs.09-4744

Cited by 94 publications

(99 citation statements)

References 47 publications

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“…14 In addition to cool temperatures, cool cell activity is increased by the application of menthol, the transient receptor potential melastatin-8 (TRPM8) agonist, and by the application of hypertonic artificial tears to the cornea. 10,12,15,16 The TRPM8 channel is a thermally gated, nonselective cation channel that is activated by moderate cold (15-308C) and by compounds, such as menthol.…”

Section: Resultsmentioning

confidence: 99%

“…[18][19][20] Previously, our laboratory reported that cool cells are activated when the ocular surface fluid status is altered by reducing the layer of artificial tears covering cornea, leading to the hypothesis that these neurons contribute to basal tearing. 15 More recently, cooling of the ocular surface in humans and mice has been shown to increase tearing. 14 Furthermore, it has been reported that TRPM8 knockout mice have a lower level of basal tear flow.…”

Section: Resultsmentioning

confidence: 99%

“…15 Briefly, the femoral artery and vein were catheterized to monitor blood pressure and deliver drugs, and a tracheotomy was performed for ventilation. End-tidal CO 2 was monitored continuously and maintained between 3.5 and 4.5%.…”

Section: Electrophysiologic Recordingsmentioning

confidence: 99%

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

Robbins

Kurose

Winterson

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Stimulation to the cornea via noxious chemical and mechanical means evokes tearing, blinking, and pain. In contrast, mild cooling of the ocular surface has been reported to increase lacrimation via activation of corneal cool primary afferent neurons. The purpose of our study was to determine whether menthol induces corneal cool cell activity and lacrimation via the transient receptor potential melastatin-8 (TRPM8) channel without evoking nociceptive responses.METHODS. Tear measurements were made using a cotton thread in TRPM8 wild type and knockout mice after application of menthol (0.05-50 mM) to the cornea. In additional studies, nocifensive responses (eye swiping and lid closure) were quantified following cornea menthol application. Trigeminal ganglion electrophysiologic single unit recordings were performed in rats to determine the effect of low and high concentrations of menthol on corneal cool cells. RESULTS.At low concentrations, menthol increased tear production in TRPM8 wild type and heterozygous animals, but had no effect in TRPM8 knockout mice, while nocifensive responses remained unaffected. At the highest concentration, menthol (50 mM) increased tearing and nocifensive responses in TRPM8 wild type and knockout animals. A low concentration of menthol (0.1 mM) increased cool cell activity, yet a high concentration of menthol (50 mM) had no effect.CONCLUSIONS. These studies indicated that low concentrations of menthol can increase lacrimation via TRPM8 channels without evoking nocifensive behaviors. At high concentrations, menthol can induce lacrimation and nocifensive behaviors in a TRPM8 independent mechanism. The increase in lacrimation is likely due to an increase in cool cell activity. (Invest Ophthalmol Vis Sci. 2012;53:7034-7042)

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Robbins

Kurose

Winterson

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…Cold thermoreceptors are the most recently described fibers responding to a reduction in temperature (eg, evaporative cooling, cold). 32,33 Transient receptor protein (TRP) channels are found in the terminal cell membranes of nociceptors and are responsible for detecting these various stimuli. For example, TRPV1 channels detect a variety of noxious stimuli including abnormal pH, heat, and chemicals.…”

Section: Dry Eye As a Pain Disordermentioning

confidence: 99%

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

Galor

Levitt

Felix

et al. 2014

Eye

182

187

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Dry eye has gained recognition as a public health problem given its prevalence, morbidity, and cost implications. Dry eye can have a variety of symptoms including blurred vision, irritation, and ocular pain. Within dry eyeassociated ocular pain, some patients report transient pain whereas others complain of chronic pain. In this review, we will summarize the evidence that chronicity is more likely to occur in patients with dysfunction in their ocular sensory apparatus (ie, neuropathic ocular pain). Clinical evidence of dysfunction includes the presence of spontaneous dysesthesias, allodynia, hyperalgesia, and corneal nerve morphologic and functional abnormalities. Both peripheral and central sensitizations likely play a role in generating the noted clinical characteristics. We will further discuss how evaluating for neuropathic ocular pain may affect the treatment of dry eye-associated chronic pain.

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“…It has been shown that the application of NaCl, capsicum, and nicotine into the corneal surface produce a vigorous response in the nociceptive neurons in the trigeminal subnucleus caudalis in rat [20]. Hyperosmotic solution like NaCl by activating transient receptor potential (TRP) vanilloid 1 and TRP melastatin 8 receptors on corneal nociceptors could induce chemical nociception [21,22].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Histamine H1 Receptor Antagonists on the Morphine-Induced Antinociception in the Acute Trigeminal Model of Nociception in Rats

Khalilzadeh

Azarpey

Hazrati

2016

Asian J Pharm Clin Res

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Objective: In this study, the effect of different classes of histamine H 1 receptor antagonists (chlorpheniramine, cetirizine, and fexofenadine), µ opioid receptor agonist (morphine), and opioid receptor antagonist (naloxone) in separate and combined treatments were investigated on the acute trigeminal model of pain in rats.Methods: Eye wiping test used for induction of acute trigeminal pain by putting a drop of NaCl, 5 M solution (40 µl) on the corneal surface of the eye, and the number of eye wipes counted during the first 30 seconds.Results: Intraperitoneal injection of both chlorpheniramine and cetirizine at doses of 10 and 20 mg/kg significantly inhibited the acute trigeminal pain. However, fexofenadine did not change corneal pain response. Morphine at doses of 1.25, 2.5, and 5 mg/kg reduced eye wipe responses. Administration of both chlorpheniramine and cetirizine but not fexofenadine before morphine-enhanced morphine analgesic activity, also pretreatment of animals with naloxone inhibited morphine, chlorpheniramine, and cetirizine-induced analgesia in the acute corneal pain. Conclusion:Our results showed that chlorpheniramine as a histamine H 1 antagonist that efficiently Penetrates blood-brain barrier (BBB) and cetirizine with less penetration of BBB but not fexofenadine (an H 1 receptor antagonist with a negligible brain-accessibility) could induce analgesia in the acute corneal pain via opioidergic mechanism. Coadministration of morphine with chlorpheniramine or cetirizine could enhance its analgesic activity in the acute trigeminal model of pain in rats.

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Cold-Sensitive Corneal Afferents Respond to a Variety of Ocular Stimuli Central to Tear Production: Implications for Dry Eye Disease

Cited by 94 publications

References 47 publications

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

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

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

The Effect of Histamine H1 Receptor Antagonists on the Morphine-Induced Antinociception in the Acute Trigeminal Model of Nociception in Rats

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