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.

Keywords: cornea; dry eye; lacrimation; trigeminal ganglion; trigeminal nucleus.

Figure 1

Activation of nociceptors innervating the cornea, nasal mucosa and oral mucosa induces secretion and nociceptive responses, including pain sensation. In contrast, cold receptors, activated by evaporative cooling of the ocular surface, increases secretion without evoking nociceptive responses. Cold and nociceptor evoked secretion is regulated by neurons located at the transition between subnucleus interpolaris and caudalis (Vi/Vc) in the spinal trigeminal nucleus (Vsp), whereas nociceptive responses are controlled by neurons located at Vc and the first cervical vertebra (C1).

Figure 2

Model for neural control of lacrimation. Corneal primary afferent neurons express a range of membrane channels, which corresponds to their physiological characteristics. The primary afferent neurons innervating the cornea regulate secretion of basal tearing with a relay through the spinal trigeminal nucleus. It has been proposed that polymodal nociceptors express channels responding to noxious chemical, thermal, and mechanical stimulation, including TRPV1, TRPA1, TRPV4, and acid sensing ion channels (ASIC) channels. In contrast, cold receptors express TRPM8 channels, which are sensitive to innocuous cooling. The channels responsible for mechanical responses in mechanoreceptive neurons and hyperosmotic responses in cold receptors have yet to be identified. PPG: Pterygopalatine ganglion