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From the Centre for Contact Lens Research, School of Optometry, University of Waterloo, Canada.
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Abstract |
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METHODS. Ten healthy human subjects participated in the study. The Belmonte pneumatic esthesiometer was used to apply mechanical and chemical stimuli to the central cornea and temporal conjunctiva of the left eye. Stimuli were applied in a paired and unpaired way for conjunctival stimulation. A 100-point visual analog scale (VAS) was used to rate the intensity of the stimulus.
RESULTS. The magnitudes of the sensation evoked from the conjunctiva were different when using different methods for presenting stimuli to the ocular surface. When stimuli were applied to the conjunctiva alone, the magnitude of the sensation was stronger than when the stimuli were applied in pairs to the cornea and conjunctiva for both mechanical (P = 0.04) and chemical (P = 0.02) stimulation.
CONCLUSIONS. The relatively strong discomfort evoked from the cornea appears to suppress partially the relatively weaker conjunctival stimulation. This manifested as the conjunctival sensory transducer function being shallower (less intense sensation) when immediately preceded by corneal stimulation than when the conjunctival sensory transducer functions were measured alone (unpaired). The underlying mechanism could be adaptation or some other inhibitory effect, such as diffuse noxious inhibitory control. At some level therefore, corneal and conjunctival sensory channels are not independent.
The cornea and conjunctiva are innervated by the trigeminal nerve. The sensory nerves are from the ciliary branch of the ophthalmic division of the trigeminal nerve and radially enter the cornea at the middle stromal level, forming the highest sensory innervation density in the body.5 6 7 The conjunctiva is innervated by a plexiform network of sensory fibers originating from branches of the ophthalmic and the maxillary nerves of the trigeminal nerve.8 9 In addition to free nerve terminals, the exclusive nerve endings in the cornea, there are encapsulated nerve endings in the conjunctiva, with the higher density in the limbal conjunctiva.10 11 12
Anatomically, the ocular surface sensory nerves belong to myelinated (A
-) and unmyelinated (C-) fiber groups. They respond to mechanical, chemical and thermal stimulation, and, functionally, these nerves are identified as polymodal nociceptors, mechanoreceptors, mechano-nociceptors and cold receptors.13 14 The mechano-nociceptor and polymodal nociceptors generally have large receptive fields in the cornea that could cover the adjacent episclera, whereas cold receptors have relatively small receptive fields. The mechanosensory nerves are the most common of the sensory nerve endings in the conjunctiva, with small receptive fields (Aracil A, et al. IOVS 2001;42:ARVO Abstract 662).
In cat and rat, nociceptive-specific or wide-dynamic-range neurons have been identified as corneal responsive neurons in the spinal trigeminal nucleus.15 16 17 18 At the transition between the subnucleus interpolaris and caudalis (Vi/Vc) and the most caudal portions of Vc at the spinomedullary junction (Vc/C1), most of these corneal responsive neurons (85%) have large receptive fields. At the Vi/Vc transition region, the corneal responsive neurons may be important in recruiting descending antinociceptive controls.18
Although the functional characteristics of corneal and conjunctival peripheral sensory nerves and second-order corneal responsive neurons at the spinal cord level have been identified in rat and cat, psychophysical examination of the interaction between corneal and conjunctival sensory channels in humans has never been undertaken. Therefore, we designed this study to begin to understand how corneal and conjunctival sensory channels respond to mechanical and chemical stimulation at suprathreshold levels.
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Methods |
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Subjects
One female and nine male (age range, 21–40 years) healthy subjects participated in this experiment. None wore contact lenses, and they had no ocular or systemic diseases.
The Belmonte Pneumatic Esthesiometer
The device has been described in detail previously.19 20 Briefly, two flow controllers regulated the air and CO2 flow rate. Two manual digital controllers set the total flow rate and the concentration of CO2. A temperature sensor was built inside the nozzle assembly allowing temperature control, and a solenoid valve inside the nozzle controlled the duration of the stimulus. The distance between the ocular surface and the esthesiometer tip was monitored by a calibrated video camera that displayed this distance on a TV screen.
Psychophysical Methods: Stimuli and Sensory Scaling
For mechanical stimulation, the flow rates were (in random order) 80, 100, 120, 140, 160, 180, and 200 mL/min. For chemical stimulation, the flow rate was set at 30 mL/min (approximately half of the corneal mechanical threshold), and the concentrations of CO2 were (in random order) 30% to 40%, 50%, 60%, 70%, 80%, 90%, and 100%. A 100-point visual analog scale (VAS) was used to rate the intensity of the stimulus. The temperature of the stimulus was set at 50°C and decreased to 
33°C at the ocular surface.19 21
Procedure
All the subjects received training by repeatedly performing the scaling procedure before the formal experiment. Measurements were made at the central cornea and the temporal bulbar conjunctiva, 5 mm away from the limbus along the horizontal meridian. For central corneal measurements, subjects viewed a target with the untested eye, and the investigator positioned the esthesiometer tip to stimulate the central cornea. For temporal conjunctival testing, the 5-mm distance between the limbus and temporal conjunctiva was estimated by the operator.
The conjunctival suprathreshold response to mechanical and chemical stimulation was performed in two ways. The lowest and highest stimuli were presented on the cornea initially, and subjects were informed that these were least and most intense. Stimuli were delivered first to the cornea and then the conjunctiva (pairings were not known to the subjects), with the conjunctival stimulus being physically the same as the preceding corneal stimulus. The intensity of the pairs of stimuli was randomly ordered. For the second suprathreshold scaling measurement, after the lowest and highest stimuli were applied to the cornea to demonstrate the minimum and maximum stimuli, they were applied in random order to the conjunctiva only. In both experiments, the subjects were asked to rate the intensity of the sensation. The weakest sensation was rated 0 and the very intense sensation, 100. Each trial was presented three times for chemical sensory scaling and twice for mechanical scaling.
Statistical Analysis
The sign test was used to evaluate statistical significance (P < 0.05). Nonlinear regression was used to fit corneal scaling transducer data with ogival functions.
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Results |
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Discussion |
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Adaptation refers to a neural response with decreased firing rate and attenuated magnitude in responding to a repeated application of a stimulus.13 22 23 It is an intrinsic characteristic of sensory pathways and occurs in both peripheral and central nervous systems.14 24 25 26 In the present study, the sensations evoked from the cornea were discomfort or irritation with both mechanical and chemical stimulation, suggesting that mechano-nociceptor or polymodal nociceptors mediated the response. In cat, the receptive fields of corneal central polymodal neurons cover approximately one fourth of the corneal central area, whereas the peripheral neurons extend to the adjacent episclera.13 Although humans may share similar receptive field characteristics on the received field of corneal sensory nerves, it is unlikely that the nerves at the temporal conjunctiva, 5 mm away from the limbus, would be affected by central corneal stimulation. Therefore, peripheral nerve adaptation does not seem to be solely responsible for the phenomenon found in this study.
The afferent information of the ocular surface sensory system is delivered by corneal and conjunctival A and C nerve fibers to the trigeminal ganglia, which convey nociceptive information to the spinal trigeminal nucleus that descends as far as the second cervical level. In lamina I of the dorsal horn, nociception-specific neurons and polymodal nociceptive neurons respond to the nociceptive stimulation conveyed by A and C sensory nerves. The nociceptive information is then integrated by wide-dynamic-range neurons in lamina V.27 The second-order corneal responsive neurons in the spinal trigeminal nucleus (Vsp) have been identified as nociception-specific or wide-dynamic-range neurons.15 16 17 18 Electrophysiological studies have shown that one of the characteristics of neurons at the transition between the subnucleus interpolaris and caudalis (Vi/Vc) and the most caudal portions of Vc at the spinomedullary junction (Vc/C1) is that they have large receptive fields. These so-called corneal-cutaneous neurons may extend their receptive fields to the adjacent cutaneous tissue, such as conjunctiva, eyelid skin, and other facial skin.13 16 18 In addition, they exhibit fatigue or adaptation to repeated stimulation. If these nerves were processing the stimuli in our experiment, the corneal-cutaneous neurons may also have responded to conjunctival stimulation and, when the paired stimuli were presented to cornea and conjunctiva, these neurons may have adapted to the corneal stimulation and become less responsive to subsequent conjunctival stimulation.
These corneal responsive neurons at the Vi/Vc transition region may also play an important role in integrating the descending antinociceptive control.18 Diffuse noxious inhibitory control involving descending inhibition from the brain stem on the dorsal horn neurons28 29 30 may be one such possible mechanism to account for the findings in our experiment. This effect has been demonstrated in the trigeminal nerve,31 32 and the depressive effect is especially apparent at high stimulus intensities.33 If this mechanism were operating in this experiment, it would result in the noxious corneal stimulation regulating the conjunctival response.
When fitted with power functions, corneal mechanical and chemical sensory transducer functions were similar to previous reports,20 34 35 as might be expected based on the Stevens power law.36 Compared with other non-nociceptive sensory modalities such as vision, warmth, and pressure in the skin,37 the exponents in the present study were high, perhaps because, in the cornea, both mechanical and chemical stimuli evoke nociceptive responses. This effect is similar to the transducer functions generated by other nociceptive stimuli, such as electrical shock, painful cold, and labor pain, each of which has been shown to have a high exponent of their respective transducer power functions.37 38 39
In summary, this study demonstrated that mechanical and chemical stimulation of the human cornea could suppress conjunctival sensation. This "negative interaction" may occur because of adaptation within the sensory system, diffuse noxious inhibitory control, or other inhibitory mechanisms. At some level, corneal and conjunctival sensory channels are not independent.
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Acknowledgements |
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Footnotes |
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Submitted for publication October 7, 2004; revised December 3, 2004; accepted December 16, 2004.
Disclosure: Y. Feng, None; T.L. Simpson, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Trefford L. Simpson, Centre for Contact Lens Research, School of Optometry, University of Waterloo, 200 University Ave. West, Waterloo, Ontario N2L 3G1, Canada; tsimpson{at}sciborg.uwaterloo.ca.
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