Report of the Neurobiology Subcommittee

Members: Fiona Stapleton (Co-Chair & SC Liason)Carl MarfurtBlanka GolebiowskiMark Rosenblatt (Co-Chair)David BereiterCarolyn BegleyDarlene DarttJuana GallarCarlos BelmontePedram HamrahMark Willcox (Harmonization Subcommittee)

Neurobiology Subcommittee

Scope:•Anatomy and morphological characteristics•Molecular and cellular neurobiology of ocular discomfort and pain. •Limited data on neurobiology of CL wear, evidence generated for dry eye disease was examined.

– Inflammatory pathway, impact of hyperosmolarity, peripheral and central mediators of ocular sensation.

– Stimulus delivered by CL & how this might impact those peripheral and central processes

•Neurobiological view of potential treatments.•Areas of future research identified.

Neurobiology Subcommittee

Sensory nerves:•Area of the ocular surface which interacts with the CL•Anatomy, morphology and neurochemistry•Corneal innervation is well characterised; limited information on conjunctiva & eyelid margin1,2

•Human corneal sensory neuropeptides predominantly CGRP & substance P3

•No evidence yet that CLD impacts morphology or neurochemistry

Neurobiology Subcommittee

Neurophysiology & sensation - PNS:• Functional types of ocular sensory neurons4

• Polymodal nociceptors (70%)• Mechano-nociceptors (15-20%)• Cold-sensitive receptors (10-15%)

• Sensitisation of polymodal & cold nociceptors•Transduction /coding of stimuli modulated by many ion channels5

• Transient Receptor Protein (TRP) Channels – polymodal activation

• Others ; Acid Sensing Ion Channels (ASICs) and K+ channels

Neurobiology Subcommittee

Neurophysiology & sensation - PNS:•Relationship with sensation?– Ion channels not functionally associated with

nociceptor type5

– Stimulus is encoded based on combination of different ion channels in each neuronal type

– Abnormal peripheral signalling may occur with persistent stimulation or inflammation - conceivable in CLD.

– Evidence in CLD limited. Increased conjunctival mechanical sensitivity in symptomatic CL wear6; altered response to suprathreshold stimuli7

Neurobiology Subcommittee

Neurophysiology & sensation: CNS: •Complex nature of perceptions suggests integration at higher brain centres

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Neurobiology Subcommittee

Factors Stimulus modality

Transduction channels Sensory neurons

CNS2nd-order neurons

Sensations

CL associated factors

Fit MovementEdge

Mechanical SA, TRPV1, TRPA1ASICs 1,3

Polymodal nociceptorLT and HT

mechanoreceptor

WDRHT

mechanoreceptor

Irritation, foreign body, grittiness

Drying

Osmolarity TRPV1-4, TRPA1, TRPC5 TRPM3, ASIC3

Polymodal nociceptor LT

mechanoreceptorWDR

HT mechanoreceptor

Dryness, irritation,

stinging, burning

Cooling TRPM8, TRPA1, K2P Cold thermoreceptor Coolness

Shrinking(mechanical)

SA, TRPV1, TRPA1, ASIC1-3

Polymodal nociceptor Irritation, grittiness

Eyelid over CL surface

Mechanical SA, TRPA1, TRPV1 ASICs 1,3

Polymodal nociceptor

LT and HT mechano-receptor

WDRHT

mechanoreceptor

Irritation, foreign body, grittiness

Solution associated factors Chemical TRPV1, TRPA1, ASICs,

Polymodal nociceptor

WDRHT

mechanoreceptorIrritation, burning

Inflammation Chemical

TRPV1, TRPA1, ASIC3, P2X, K+

Polymodal nociceptor

MIA

WDRHT

mechanoreceptor

Irritation, burning, stinging,

TRPM8, GPCR Cold thermoreceptorMIA

WDRHT

mechanoreceptor

Coolness, cold pain, itch

Summary of the neurophysiology of CLD

Neurobiology Subcommittee

Treatments (neurobiological targets):•Reduce mechanical stimulation

– Alter materials, change friction modulus8,9

– Reduce mechanical insult to the conjunctiva9

•Chemical– Reduce activation/sensitization of polymodal nociceptors10

– Control pH & osmolarity known to activate receptors11

– Limit dehydration12

•Pharmacological agents– Neuropathic pain, altered excitability of corneal nerves13

– Others, e.g. NGF to treat nerve architecture or αNGF manage symptomatology14

Neurobiology Subcommittee

Future directions for research:•Pain/discomfort questionnaires•Morphological and functional studies•Animal Models– Contact lens wear– Pain models

•Natural history or chronicity of discomfort

Neurobiology Subcommittee

Summary:• Corneal nerves only well studied• Current understanding of ocular surface sensation is incomplete• Relevant aspects of CL wear in CLD:

− physical interaction with ocular surface− hyperosmolarity− chemical mediators in MPS/packaging solutions− inflammatory mediators

− Sensory changes due to neural adaptation to a continuous stimulus or neural sensitization in response to hyperosmolarity or inflammatory mediators

Neurobiology Subcommittee

Summary:• Future directed treatments

– Lens related factors– Agents to modulate peripheral & central nervous system

responses

• Development of sensitive measurement & analytical techniques at all stages of discomfort pathway.

Thank you!

QUESTIONS?

Neurobiology Subcommittee

Key References:1. Al-Aqaba MA, Fares U, Suleman H, Lowe J, Dua HS. Architecture and

distribution of human corneal nerves. Br J Ophthalmol 2010;94:784-789.2. Bron AJ, Tripathi, R., and Tripathi, B. Wolff's Anatomy of the Eye and Orbit. 8th

ed. London: Chapman and Hall Medical; 1997.3. Marfurt CF. Peptidergic innervation of the cornea: anatomical and functional

consideration. In: Troger JaK, G. (ed), Neuropeptides in the Eye. Kerala: Research Signpost; 2009:23-37.

4. Belmonte C, Aracil A, Acosta MC, Luna C, Gallar J. Nerves and sensations from the eye surface. Ocul Surf 2004;2:248-253.

5. Viana F, Belmonte C. Transduction and encoding of noxious stimulus. In: Schmidt RF, Gebhart GF (eds), Encyclopedia of Pain: Springer; 2013.

6. Tan et al., IOVS 1997; 38 ARVO abstract S13367. Chen J, Simpson TL. A role of corneal mechanical adaptation in contact lens-

related dry eye symptoms. Invest Ophthalmol Vis Sci 2011;52:1200-1205.8. Holden BA, Stephenson A, Stretton S, et al. Superior epithelial arcuate lesions

with soft contact lens wear. Optom Vis Sci 2001;78:9-12.

Neurobiology Subcommittee

Key References:9. Santodomingo-Rubido J, Wolffsohn J, Gilmartin B. Conjunctival epithelial flaps

with 18 months of silicone hydrogel contact lens wear. Eye Contact Lens 2008;34:35-38.

10. Lazon de la Jara P, Papas E, Diec J et al. Effect of lens care systems on the clinical performance of a contact lens. Optom Vis Sci 2013;90:344-350.

11. Stahl U, Willcox M, Stapleton F. Role of hypo-osmotic saline drops in ocular comfort during contact lens wear. Contact Lens Ant Eye 2010;33:68-75.

12. Peterson RC, Wolffson JS, Nick J et al. Clinical performance of daily disposable soft contact lenses using sustained release technology. Contact Lens Ant Eye 2006;29:137-134.

13. Lichtinger A, Purcell TL, Schanzlin DJ, Chayet AS. Gabapentin for postoperative pain after photorefractive keratectomy: a prospective, randomized, double-blind, placebo-controlled trial. J Refract Surg 2011;27:613-617.

14. Eibl JK, Strasser BC, Ross GM. Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int 2012;61:1266-1275.