Diapositiva 1

1
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)
2
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.

3
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

4
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

5
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

6
Neurobiology Subcommittee

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

7
Neurobiology Subcommittee
Summary of the neurophysiology of CLD
Factors Factors Stimulus modality Transduction channels Sensory neurons CNS 2nd-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
CL associated factors Drying           Osmolarity TRPV1-4, TRPA1, TRPC5 TRPM3, ASIC3 Polymodal nociceptor LT mechanoreceptor WDR HT mechanoreceptor Dryness, irritation, stinging, burning
CL associated factors Drying           Cooling TRPM8, TRPA1, K2P Cold thermoreceptor LT mechanoreceptor WDR HT mechanoreceptor Coolness
CL associated factors Drying           Shrinking (mechanical) SA, TRPV1, TRPA1, ASIC1-3 Polymodal nociceptor LT mechanoreceptor WDR HT mechanoreceptor Irritation, grittiness
CL associated factors 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 Solution associated factors Chemical TRPV1, TRPA1, ASICs, Polymodal nociceptor WDR HT mechanoreceptor Irritation, burning
Inflammation Inflammation Chemical TRPV1, TRPA1, ASIC3, P2X, K Polymodal nociceptor MIA WDR HT mechanoreceptor Irritation, burning, stinging,
Inflammation Inflammation Chemical TRPM8, GPCR Cold thermoreceptor MIA WDR HT mechanoreceptor Coolness, cold pain, itch
8
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
  aNGF manage symptomatology14

9
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

10
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

11
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.

12
Thank you!
QUESTIONS?
13
Neurobiology Subcommittee

• Key References
• Al-Aqaba MA, Fares U, Suleman H, Lowe J, Dua HS.
  Architecture and distribution of human corneal
  nerves. Br J Ophthalmol 201094784-789.
• Bron AJ, Tripathi, R., and Tripathi, B. Wolff's
  Anatomy of the Eye and Orbit. 8th ed. London
  Chapman and Hall Medical 1997.
• Marfurt CF. Peptidergic innervation of the
  cornea anatomical and functional consideration.
  In Troger JaK, G. (ed), Neuropeptides in the
  Eye. Kerala Research Signpost 200923-37.
• Belmonte C, Aracil A, Acosta MC, Luna C, Gallar
  J. Nerves and sensations from the eye surface.
  Ocul Surf 20042248-253.
• Viana F, Belmonte C. Transduction and encoding of
  noxious stimulus. In Schmidt RF, Gebhart GF
  (eds), Encyclopedia of Pain Springer 2013.
• Tan et al., IOVS 1997 38 ARVO abstract S1336
• Chen J, Simpson TL. A role of corneal mechanical
  adaptation in contact lens-related dry eye
  symptoms. Invest Ophthalmol Vis Sci
  2011521200-1205.
• Holden BA, Stephenson A, Stretton S, et al.
  Superior epithelial arcuate lesions with soft
  contact lens wear. Optom Vis Sci 2001789-12.

14
Neurobiology Subcommittee

• Key References
• Santodomingo-Rubido J, Wolffsohn J, Gilmartin B.
  Conjunctival epithelial flaps with 18 months of
  silicone hydrogel contact lens wear. Eye Contact
  Lens 20083435-38.
• 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 201390344-350.
• Stahl U, Willcox M, Stapleton F. Role of
  hypo-osmotic saline drops in ocular comfort
  during contact lens wear. Contact Lens Ant Eye
  20103368-75.
• Peterson RC, Wolffson JS, Nick J et al. Clinical
  performance of daily disposable soft contact
  lenses using sustained release technology.
  Contact Lens Ant Eye 200629137-134.
• 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 201127613-617.
• Eibl JK, Strasser BC, Ross GM. Structural,
  biological, and pharmacological strategies for
  the inhibition of nerve growth factor. Neurochem
  Int 2012611266-1275.