Concurrent ocular pain in patients with neurotrophic keratopathy

Abstract Background Dry eye disease (DED) is a multifactorial disease of the ocular surface accompanied by neurosensory abnormalities. Here, we evaluated the effectiveness of transient receptor potential vanilloid-1 (TRPV1) blockade to alleviate ocular pain, neuroinflammation, and anxiety-like behavior associated with severe DED. Methods Chronic DED was induced by unilateral excision of the Harderian and extraorbital lacrimal glands of adult male mice. Investigations were conducted at 21 days after surgery. The mRNA levels of TRPV1, transient receptor potential ankyrin-1 (TRPA1), and acid-sensing ion channels 1 and 3 (ASIC1 and ASIC3) in the trigeminal ganglion (TG) were evaluated by RNAscope in situ hybridization. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous and stimulated (cold, heat, and acid) corneal nerve responsiveness in ex vivo eye preparations. DED mice received topical instillations of the TRPV1 antagonist (capsazepine) twice a day for 2 weeks from d7 to d21 after surgery. The expression of genes involved in neuropathic and inflammatory pain was evaluated in the TG using a global genomic approach. Chemical and mechanical corneal nociception and spontaneous ocular pain were monitored. Finally, anxiety-like behaviors were assessed by elevated plus maze and black and white box tests. Results First, in situ hybridization showed DED to trigger upregulation of TRPV1, TRPA1, ASIC1, and ASIC3 mRNA in the ophthalmic branch of the TG. DED also induced overexpression of genes involved in neuropathic and inflammatory pain in the TG. Repeated instillations of capsazepine reduced corneal polymodal responsiveness to heat, cold, and acidic stimulation in ex vivo eye preparations. Consistent with these findings, chronic capsazepine instillation inhibited the upregulation of genes involved in neuropathic and inflammatory pain in the TG of DED animals and reduced the sensation of ocular pain, as well as anxiety-like behaviors associated with severe DED. Conclusion These data provide novel insights on the effectiveness of TRPV1 antagonist instillation in alleviating abnormal corneal neurosensory symptoms induced by severe DED, opening an avenue for the repositioning of this molecule as a potential analgesic treatment for patients suffering from chronic DED.

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Topical TRPM8 Agonist for Relieving Neuropathic Ocular Pain in Patients with Dry Eye: A Pilot Study

Journal of Clinical Medicine ◽

10.3390/jcm10020250 ◽

2021 ◽

Vol 10 (2) ◽

pp. 250

Author(s):

Hyeon Jeong Yoon ◽

Jonghwa Kim ◽

Jee Myung Yang ◽

Edward T. Wei ◽

Seong Jin Kim ◽

...

Keyword(s):

Quality Of Life ◽

Pilot Study ◽

Pain Intensity ◽

Dry Eye ◽

Associated Factors ◽

Treatment Result ◽

Ocular Pain ◽

Eye Pain ◽

Validated Questionnaire

Background: Activation of TRPM8, a cold-sensing receptor located on the cornea and eyelid, has the potential to relieve the neuropathic ocular pain (NOP) in dry eye (DE) by inhibiting other aberrant nociceptive inputs. We aimed to investigate the effect of a topical TRPM8 agonist, cryosim-3 (C3), on relieving DE-associated NOP. Methods: We conducted a prospective pilot study of 15 patients with DE-associated NOP. These patients applied topical C3 to their eyelid, 4 times/day for 1 month. The patients underwent clinical examinations. They also completed the Ocular Pain Assessment Survey (OPAS), which is a validated questionnaire for NOP, at baseline, 1 week, and 1 month after treatment. Result: At 1 week, the OPAS scores of eye pain intensity, quality of life (driving/watching TV, general activity, sleep, and enjoying life/relations with other people), and associated factors (burning sensation, light sensitivity, and tearing) improved. The total OPAS scores of eye pain intensity, quality of life, and associated factors remained improved at 1 month. The Schirmer test scores also improved at 1 month. Conclusion: TRPM8 agonist (C3) could be a novel agent for treating patients with DE-associated NOP who are unresponsive to conventional treatments.

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Neuropathic-Like Ocular Pain and Nonocular Comorbidities Correlate With Dry Eye Symptoms

Eye & Contact Lens Science & Clinical Practice ◽

10.1097/icl.0000000000000463 ◽

2018 ◽

Vol 44 ◽

pp. S307-S313 ◽

Cited By ~ 3

Author(s):

Victoria S. Chang ◽

Terri P. Rose ◽

Carol L. Karp ◽

Roy C. Levitt ◽

Constantine Sarantopoulos ◽

...

Keyword(s):

Dry Eye ◽

Ocular Pain ◽

Eye Symptoms ◽

Dry Eye Symptoms

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Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms

Eye & Contact Lens Science & Clinical Practice ◽

10.1097/icl.0000000000000249 ◽

2017 ◽

Vol 43 (3) ◽

pp. 192-198 ◽

Cited By ~ 31

Author(s):

Jerry P. Kalangara ◽

Anat Galor ◽

Roy C. Levitt ◽

Derek B. Covington ◽

Katherine T. McManus ◽

...

Keyword(s):

Dry Eye ◽

Ocular Pain ◽

Eye Symptoms ◽

Dry Eye Symptoms

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Corneal neurotisation by great auricular nerve transfer and scleral-corneal tunnel incisions for neurotrophic keratopathy

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-312563 ◽

2018 ◽

Vol 103 (9) ◽

pp. 1235-1238 ◽

Cited By ~ 12

Author(s):

Nate Jowett ◽

Roberto Pineda II

Keyword(s):

Visual Acuity ◽

Confocal Microscopy ◽

Donor Site ◽

Nerve Transfer ◽

Donor Site Morbidity ◽

Nerve Fibres ◽

Novel Technique ◽

Great Auricular Nerve ◽

Early Results ◽

Neurotrophic Keratopathy

Background/AimsMedical management of neurotrophickeratopathy is challenging and costly. Supra-orbital nerve transfer to thecornea has proven effective for management of keratopathy, but yieldsconsiderable donor site morbidity. Herein, a novel technique for reinnervationof the anaesthetic cornea is presented and early results characterised.MethodsSensory fibres of the ipsilateral greatauricular nerve were directed via an interposition graft to the anteriorcorneal stroma using scleral-corneal tunnel incisions in two patients withgrade III neurotrophic keratopathy.ResultsImprovements in visual acuity, cornealpachymetry, corneal esthesiometry, and corneal neurotisation as assessed by invivo confocal microscopy were observed within nine months of surgery in bothpatients.ConclusionCorneal neurotisation by interposition grafttransfer of great auricular nerve fibres via scleral-corneal tunnel incisionsappears effective in the management of neurotrophic keratopathy.

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