Report of the Neurobiology Subcommittee Members:Fiona Stapleton (Co-Chair & SC Liason) Carl Marfurt Blanka Golebiowski Mark Rosenblatt (Co-Chair) David Bereiter Carolyn Begley Darlene Dartt Juana Gallar Carlos Belmonte Pedram Hamrah Mark 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 margin 1,2 Human corneal sensory neuropeptides predominantly CGRP & substance P 3 No evidence yet that CLD impacts morphology or neurochemistry

Neurobiology Subcommittee Neurophysiology & sensation - PNS: Functional types of ocular sensory neurons 4 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 channels 5 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 type 5 – 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 wear 6 ; altered response to suprathreshold stimuli 7

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

Neurobiology Subcommittee Factors Stimulus modality Transduction channels Sensory neurons CNS 2 nd -order neurons Sensations CL associated factors Fit Movement Edge Mechanical SA, TRPV1, TRPA1 ASICs 1,3 Polymodal nociceptor LT and HT mechanoreceptor WDR HT mechanoreceptor Irritation, foreign body, grittiness Drying Osmolarity TRPV1-4, TRPA1, TRPC5 TRPM3, ASIC3 Polymodal nociceptor LT mechanoreceptor WDR HT mechanoreceptor Dryness, irritation, stinging, burning Cooling TRPM8, TRPA1, K2PCold thermoreceptorCoolness Shrinking (mechanical) SA, TRPV1, TRPA1, ASIC1-3 Polymodal nociceptorIrritation, grittiness Eyelid over CL surface Mechanical SA, TRPA1, TRPV1 ASICs 1,3 Polymodal nociceptor LT and HT mechano- receptor WDR HT mechanoreceptor Irritation, foreign body, grittiness Solution associated factors Chemical TRPV1, TRPA1, ASICs, Polymodal nociceptor WDR HT mechanoreceptor Irritation, burning Inflammation Chemical TRPV1, TRPA1, ASIC3, P2X, K + Polymodal nociceptor MIA WDR HT mechanoreceptor Irritation, burning, stinging, TRPM8, GPCR Cold thermoreceptor MIA WDR HT mechanoreceptor Coolness, cold pain, itch Summary of the neurophysiology of CLD

Neurobiology Subcommittee Treatments (neurobiological targets): Reduce mechanical stimulation – Alter materials, change friction modulus 8,9 – Reduce mechanical insult to the conjunctiva 9 Chemical – Reduce activation/sensitization of polymodal nociceptors 10 – Control pH & osmolarity known to activate receptors 11 – Limit dehydration 12 Pharmacological agents – Neuropathic pain, altered excitability of corneal nerves 13 – Others, e.g. NGF to treat nerve architecture or αNGF manage symptomatology 14

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: Bron AJ, Tripathi, R., and Tripathi, B. Wolff's Anatomy of the Eye and Orbit. 8th ed. London: Chapman and Hall Medical; Marfurt CF. Peptidergic innervation of the cornea: anatomical and functional consideration. In: Troger JaK, G. (ed), Neuropeptides in the Eye. Kerala: Research Signpost; 2009: Belmonte C, Aracil A, Acosta MC, Luna C, Gallar J. Nerves and sensations from the eye surface. Ocul Surf 2004;2: Viana F, Belmonte C. Transduction and encoding of noxious stimulus. In: Schmidt RF, Gebhart GF (eds), Encyclopedia of Pain: Springer; Tan et al., IOVS 1997; 38 ARVO abstract S Chen J, Simpson TL. A role of corneal mechanical adaptation in contact lens- related dry eye symptoms. Invest Ophthalmol Vis Sci 2011;52: 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: 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: 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: 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: 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: Eibl JK, Strasser BC, Ross GM. Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int 2012;61: