Summary of "white papers"
by NEI Workshop on Ocular Pain and Sensitivity Participants
September 30-October 1, 2010
Prior to the meeting, each participant was asked to provide a "white paper" that summarized important recent research both in their own lab as well as by others in the field. Below, you will find a summary of the key points for discussion identified in the pre-workshop white papers.
Gaps, scientific opportunities, and unanswered questions
There are many types of ocular pain, including pain at the ocular surface, deep ocular or orbital pain, and referred pain. Different types of sensitivities may exist, including burning, itching, dry, or gritty sensations, or no sensation at all. The most common reason for discomfort at the ocular surface is categorized as dry eye.
Below, you will find a compilation of unanswered questions, gaps, and scientific opportunities identified in the pre-workshop white papers submitted by workshop participants. Several different themes arose, and they are summarized here:
- How do we classify and diagnose different ocular pain syndromes?
- Acute vs. chronic pain
- Comparisons of different pathologies
- Headache-related ocular pain, photophobia
- Anaesthetic corneas
- How do we measure and quantify pain, sensitivity, and innervation in different pathological conditions (e.g., ocular surface irritation)?
Functional innervation of the eye
- A battery of different test stimuli is needed to obtain precise information about the various types of afferent nerve fibers.
- What factors regulate re-innervation of the adult cornea after disease or injury?
- Are regenerating nerves (e.g., following LASIK) more sensitive to normal environmental stimuli?
- What are the contributions of different types of sensory nerves to the normal function of the lacrimal functional unit?
- Does chronic tear dysfunction lead to degeneration of nerve endings, corneal hypoesthesia and neurotrophic epitheliopathy?
- What are the differences between trigeminal (i.e., corneal) and spinal nociceptors?
- To what extent do neurochemically distinct corneal afferent populations differ in their electrophysiological characteristics, functional roles (discriminative nociception versus ocular surface homeostasis), susceptibility to herpes simplex infection, regenerative capacity after refractive or ocular surgery, effects of aging, and brainstem central projections?
- How does innervation of the ocular surface impact and respond to ocular surface insults including deficiency of tear components and infection?
- Coupling new technologies in corneal nerve imaging with advances in characterizing corneal nerve function is needed.
- One technical challenge for research in this field is that corneal afferents are not easily amenable to anatomical tracing.
Molecular and cellular mechanisms
- The contribution of the different functional types of ocular sensory receptors to sensation, particularly under pathological conditions (injury, inflammation, infections, and ocular dryness) is not fully established.
- The contribution of different membrane ion channels, endogenous mediators and intracellular signaling pathways to the altered activity exhibited by ocular sensory receptors under pathological conditions has to be explored.
- The neurochemical and molecular phenotypes of primary afferent nociceptive neurons, and in particular corneal and other ocular afferent neurons, remain incompletely characterized.
- What are the neural sensitizing mediators that increase in tear dysfunction states?
- Cellular and molecular changes taking place in injured [ocular] nerves need to be studied with electrophysiological, molecular biology and genetic techniques.
- To what extent do corneal nerve injuries (refractive and ocular surgeries, herpetic infections, etc.) as well as "normal aging," alter the expression of corneal afferent neuropeptides, neuroenzymes, and ion channel/receptors, and do these alterations contribute to ocular pain syndromes?
- Are the molecular transducers that are present in cutaneous afferents also present in corneal afferents, and do they mediate similar functions?
- Why do certain "dry eye" patients develop disabling eye irritation with only mild tear instability? Is this a neuropathic problem? Neuroscientists and research neurologists need to participate in exploring the model of neuropathic dry eye.
- We need to deepen our understanding of the role of central mechanisms that sustain corneal/trigeminal neuropathic pain and photophobia.
- The central circuitry and processing of corneal inputs regulating ocular surface homeostasis and pain need to be defined.
- The broader role of trigeminal-autonomic relations in ocular pain is not well defined: How do ocular surface and intraocular sensory inputs interact to modify CNS circuits that mediate ocular pain and/or homeostasis?
- Cortical representation of the eye is not well understood.
- Is ocular pain associated with specific brain reorganization, suggesting also a specific set of cognitive abnormalities?
- The functional significance of a dual representation of the eye at the level of the second-order neuron is not certain.
- How the nervous system signals itch vs. pain needs to be investigated; are different qualities of itch and pain signaled by segregated pathways, each activated by a select set of stimuli?
- The role of pain modulation system/pain perception in chronic pain states needs to be studied.
- Is corneal pain relayed through a trigeminothalamic system that is similar to the cutaneous nociceptive pathway, or is ocular pain relayed through other ascending systems, such as the parabrachial-amygdala pathway?
- Are corneal sensory neurons modulated by the same descending pathways that modulate spinal nociceptive reflex pathways?
Role of inflammation
- How do we identify the type and site of inflammation involved in ocular pain?
- Do we understand the role of inflammation in eye pain and the role of sensory nerves in inflammation?
- What is the contribution of inflammatory cells (e.g. macrophages, dendritic cells) to ocular pain? Do these cells function similar to microglia in the nervous system in amplifying the pain response?
- Can we use the cornea as a model system for studying inflammatory mechanisms of pain?
Prevention/ causes of pain
- There is a need to identify the likely genetic and epigenetic factors responsible for increasing patient susceptibility to dry eye.
- How do we work out the basic pathology in ocular and referred ocular pain? The success may be vital for the patient, at least for their vision.
- Research into the cause of eye pain in migraine and other primary headaches will shed light on the pathophysiological processes involved as well as answer questions about the risks to the eyes and optic nerves in these conditions.
- Why does the transition from acute to chronic pain happen in some patients but not in others? Understanding this might lead to more effective prevention strategies.
- Can we develop safe pharmacological interventions for modulating ocular surface pain that restore the integrity of the ocular surface?
- Should treatment of corneal hyperesthesia include agents to reduce neural sensitivity?
- Can we manage ocular pain without affecting corneal healing? Study of inflammatory hyperalgesia may help provide new tools for pain management during corneal healing.
- There is a continued need to identify and characterize the receptors and ion channels that transduce or conduct nociceptive stimuli from the ocular surface (e.g., TRPV1 ion channels, ASICs, P2X channels, bradykinin B1 or B2 receptors, voltage gate sodium channel 1.8 (Nav1.8), etc). These molecules represent potential targets for the development of new drugs that reduce acute ocular pain and/or interfere with peripheral nociceptor sensitization.
- The potential of central electrical neuromodulation interventions should be explored.
- New topical drugs need to be developed that suppress corneal ectopic discharges and neurogenic (and other) inflammation more effectively and selectively.
- What are the effects of long-term treatment with artificial tears? Are there other ways to deal with tear deficiency?