The role of corneal afferent neurons in regulating tears under normal and dry eye conditions

Abstract

The cornea is one of several orofacial structures requiring glandular secretion for proper lubrication. Glandular secretion is regulated through a neural reflex initiated by trigeminal primary afferent neurons innervating the corneal epithelium. Corneal sensory afferents must respond to irritating and potentially damaging stimuli, as well as drying that occurs with evaporation of the tear film, and the physiological properties of corneal afferents are consistent with these requirements. Polymodal neurons are sensitive to noxious mechanical, thermal and chemical stimuli, mechanoreceptive neurons are selectively activated by mechanical stimuli, and cool cells respond to innocuous cooling. The central terminations of corneal primary afferents are located within two regions of the spinal trigeminal nucleus. The more rostral region, located at the transition between the trigeminal subnucleus caudalis and interpolaris, represents a critical relay for the regulation of the lacrimation reflex. From this region, major control of lacrimation is carried through projections to preganglionic parasympathetic neurons located in or around the superior salivatory nucleus. Dry eye syndrome may be caused by a dysfunction in the tear secreting glands themselves or in the neuronal circuit regulating these glands. Furthermore, the dry eye condition itself may modify the properties of corneal afferents and affect their ability to regulate secretion, a possibility just now being explored.

The potential role of neuropathic mechanisms in dry eye syndromes

“…For example, through the activation of transient receptor potential M8 channels, 18 innocuous stimulation with mild cooling activates corneal afferents and induces tearing without causing irritation or pain 5 . That cold receptor activation appears to evoke secretion of tears without accompanying pain 18 is supported by the finding that they are the only corneal primary afferent neuron with spontaneous activity at room temperature 19 . Sensations evoked by mechano- and polymodal nociceptors always include an irritation component 4 .…”

“…Sensory innervation of the cornea is essential for detecting environmental stressors and, through brain stem circuits, for regulating the flow of glandular secretion 18 . Glandular secretions from lacrimal, goblet cell, and Meibomian gland sources, are regulated through primary afferent projections to the spinal trigeminal nucleus 18 .…”

“…Glandular secretions from lacrimal, goblet cell, and Meibomian gland sources, are regulated through primary afferent projections to the spinal trigeminal nucleus 18 . Conjunctival and corneal epithelial cells can also modify tear composition through the secretion or absorption of electrolytes and water 18 .…”

Evidence for TRPA1 involvement in central neural mechanisms in a rat model of dry eye

“…Interestingly, exorbital gland removal alone was sufficient to produce Fos-LI at the Vi/Vc transition consistent with results seen after acute drying of the ocular surface (Hirata et al 2004). This suggested that the reduced spontaneous tear volume in our DE model (~50% reduction) was sufficient to excite ongoing activity of moisture-sensitive corneal afferent fibers that would be expected to increase during ocular surface dryness (Meng and Kurose 2013). These data support previous studies indicating that ocular stimulus intensity coding is a more pronounced feature of Vc/C1 neurons compared to Vi/Vc transition neurons (see Bereiter et al 2000), whereas the Vi/Vc transition may be more involved in homeostatic reflex responses such as lacrimation and eyeblink (Hirata et al 2004; Rahman et al 2014) and maintenance of a stable tear film.…”

Central Connections of the Lacrimal Functional Unit

“…1 This sensory input is then processed in the SSN along with inputs from other locations, to produce a graded output. 6 The parasympathetic, efferent limb of the reflex arc arises in the SSN and projects to the lacrimal and meibomian glands and to the goblet cells of the conjunctival epithelium after synapsing with third order fibres in the pterygopalatine ganglion. These third order parasympathetic neurons arise in the ipsilateral pterygopalatine ganglion; in the monkey a small input arises from the contralateral ganglion 7 but the existence of such a source in the human is not known.…”