Neuropathic Ocular Pain: An Important Yet Underevaluated Feature of Dry Eye

A Galor; RC Levitt; ER Felix; ER Martin; CD Sarantopoulos


Eye. 2015;29(3):301-312. 

In This Article

The Ocular Sensory Apparatus: Primary Nociceptors and Secondary and Tertiary Neurons

The cornea is innervated by branches of the nasociliary nerve, a branch of V1 (ophthalmic division of the trigeminal nerve). Nerve bundles enter the peripheral cornea in a radial manner and lose their myelin sheath ~1 mm from the limbus.[30] The nerves continue to branch and eventually turn 90 degrees and proceed to the corneal surface.[30,31] The unique location of the free corneal nerve endings between the cells of the superficial epithelium, very near to the ocular surface, places them in a vulnerable position to repeated damage from environmental exposures (evaporation, pollution, and so on).[26]

As reviewed by Rosenthal and Borsook,[26] different types of nociceptor (pain) fibers are found within the cornea including mechanoreceptors (~20% of total sensory population), polymodal receptors (~70% of total sensory population), and cold receptors (~10% of total sensory population). As reviewed by Belmonte and Gallar,[32] mechanoreceptors are the fastest conducting nociceptors whose peripheral endings are activated by mechanical forces. They are responsible for the sharp pain, experienced when an object touches the cornea or conjunctivae. Polymodal nociceptors are activated by mechanical forces, but also by other stimuli like heat, acidic/basic conditions, and chemicals. Cold thermoreceptors are the most recently described fibers responding to a reduction in temperature (eg, evaporative cooling, cold).[32,33]

Transient receptor protein (TRP) channels are found in the terminal cell membranes of nociceptors and are responsible for detecting these various stimuli. For example, TRPV1 channels detect a variety of noxious stimuli including abnormal pH, heat, and chemicals.[34] TRPM8, on the other hand, detects small temperature drops on the ocular surface and is thus able to sense evaporative changes in the tear film.[35] In this manner, this channel is believed to be involved in regulating basal tearing. In mice lacking TRPM8 channels, cold thermoreceptors did not fire spontaneously and did not increase their firing rate with temperature drops. These mice had abnormally low basal tearing but normal tearing in response to other noxious stimuli. A similar correlate was found in healthy volunteers who displayed decreased tearing at 43 °C compared with 18 and 25 °C (n=11).[35]

Corneal nociceptors have their primary cell bodies in the trigeminal ganglion and first synapse in the trigeminal subnucleus interpolaris/subnucleus caudalis (Vi/Vc) transition zone, and in the subnucleus caudalis/upper cervical transition zone (Vc/C1–2) (Figure 1).[36,37] From the spinal trigeminal nuclear complex, second-order axons decussate and join the contralateral spinothalamic pathways and synapse in the thalamus. Third-order neurons then relay information to the supra-spinal centers, including the somatosensory cortex. Perception of pain is also simultaneously modified by descending pain pathways.[28] Signals are transmitted from the limbic system and midbrain through the periaqueductal grey to the brainstem, where signals are modulated, and then continue back to the trigeminal subnucleus caudalis.

Figure 1.

A simplified version of the ocular sensory pathway. First-order neuron (solid line) with nerve ending in the cornea, cell body in the trigeminal ganglion, and synapse in the subnucleus caudalis. In actuality, however, there are multiple synapses for each nociceptor in the trigeminal subnucleus interpolaris/subnucleus caudalis (Vi/Vc) transition zone, and in the subnucleus caudalis/upper cervical transition zone (Vc/C1–2). Second-order neurons (dashed line) decussate and join the contralateral spinothalamic pathways and synapse in the thalamus. Third-order neurons (dashed line) then relay information to the supraspinal centers, including the somatosensory cortex. Reproduced with permission from Rosenthal and Borsook.26

The above schema is an undoubtedly simplified version of the ocular sensory apparatus. For example, dry eye patients report a variety of ocular complaints when describing their symptoms including burning, aching, dryness, grittiness, irritation, and itch. It is likely that different sensations are transmitted through slightly different pathways. For example, in rats subjected to ultraviolet irradiation-induced photokeratitis, hypertonic saline-evoked activity of ocular neurons in the Vc/C1 junction was enhanced after 2 days, but a similar correlate was not seen in the Vi/Vc transition region.[38] This suggests that the Vc/C1 region is important in pain sensation. In contrast, drying of the ocular surface affected neurons in the Vi/Vc transition as opposed to the Vc/C1 junction.[39] In a similar manner, the ocular sensation of itch has been postulated to also go through the Vi/Vc junction, as reviewed by Stapleton et al.[34] In addition, sensory nerves also innervate the conjunctiva and eyelid margins and these nerves also likely play a role in dry eye-associated ocular pain. However, less information is available on their morphology and functions.[34]