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. Author manuscript; available in PMC: 2010 Mar 17.
Published in final edited form as: Arch Ophthalmol. 2009 Nov;127(11):1468–1473. doi: 10.1001/archophthalmol.2009.270

Topical Naltrexone Reverses Dry Eye and Restores Corneal Sensation in Diabetes Mellitus

Ian S Zagon 1, Matthew S Klocek 1, Joseph W Sassani 1, Patricia J McLaughlin 1
PMCID: PMC2840396  NIHMSID: NIHMS179032  PMID: 19901212

Abstract

Objective

To determine if topical application of naltrexone (NTX), an opioid antagonist, restores tear production and corneal sensation in rats with diabetes.

Methods

Type 1 diabetes (DB) was induced with streptozotocin (STZ) in rats. Tear production was measured by the Schirmer's test, and corneal sensitivity by an aesthesiometer. Eye drops of 10−5 M NTX or sterile vehicle (SV) were administered either once only or q.i.d for 1 or 5 days; a single drop of insulin (1 U) was given once only.

Results

Dry eye and corneal insensitivity were detected in the DB rats beginning 5 weeks after STZ injection. One drop of NTX or q.i.d. for 1 or 5 days re-established tear production and corneal sensitivity within 1 hour of administration. The reversal of dry eye lasted for up to 2–3 days depending on drug regimen, but restitution of corneal sensation lasted for 4 to 7 days. Topical application of one eye drop of insulin restored corneal sensitivity within 1 hour and lasted for at least 2 days. In contrast, one eye drop of insulin did not increase tear production at 1, 24, or 48 hours compared to diabetic animals receiving SV.

Conclusions

Topical treatment with NTX normalizes tear production and corneal sensitivity in type 1 diabetic rats.

Clinical Relevance

Topical application of NTX to the ocular surface may serve as an important strategy for treating dry eye and corneal anesthesia in diabetes. Its effect, if any, in other forms of decreased corneal sensitivity and/or dry eye should be investigated.

INTRODUCTION

Diabetes mellitus often is accompanied by dry eye disease,1–3 with a significantly higher incidence reported than in nondiabetic individuals.1,4,5 Not surprisingly, diabetic patients often complain of dry eye symptoms, and may exhibit abnormal Schirmer tests, blinking rate, basal tear production, tear film, and tear film break-up time (BUT), as well as differences in the composition of tear proteins from healthy subjects.2,4,6–9 Dry eye may be accompanied by ocular surface damage, alteration in the metabolism and vitality of the epithelium, impairment of wound healing, and may lead to ulceration, and in general, can limit and degrade visual performance.10,11 Although there are multiple modalities to treat dry eye disease (e.g., punctal plugs, antinflammatory agents, topical tear and gel replacements), the etiology, management, and treatment of dry eye in diabetes remains a challenge to clinicians and researchers alike.12,13

Naltrexone hydrochloride (NTX) is an opioid antagonist that has been reported to restore corneal re-epithelialization, and prevent exuberant granulation tissue formation and corneal neovascularization in diabetic animals.14–16 An important observation documented in studies on NTX in diabetic animals with respect to the cornea relates to the well known complication of decreased sensitivity.2,9 Topical NTX administered to diabetic rats in a wide range of concentrations restored corneal sensation.17 The mechanism by which NTX acts to re-establish corneal sensitivity, or its effect, if any, in correcting dry eye, is unknown.

The present study examined the hypothesis that topical application of the opioid antagonist NTX restores tear production and corneal sensation in rats with type 1 diabetes.

METHODS

ANIMALS AND INDUCTION OF DIABETES

Male Sprague-Dawley rats (~245 g) were obtained from Charles River Laboratories (Wilmington, MA) and housed under standard laboratory conditions.14–16 All investigations conformed to the regulations of the ARVO, National Institutes of Health, and the guidelines of the Department of Comparative Medicine of The Pennsylvania State University.

Type 1 diabetes was induced according to previously reported procedures.14–16 Briefly, an intraperitoneal (i.p.) injection of 40 mg/kg streptozotocin (STZ, Sigma, St. Louis, MO) in ice-cold 0.5 mol/l citrate buffer (pH 4.5) was administered. A second dose of STZ (40 mg/kg) was injected 24 hours later. This regimen produced insulin-deficient diabetes in 100% of the animals within 48 to 72 hours; these animals were termed DB rats (n=25). Fifteen animals not receiving STZ, but injected with citrate buffer, were considered Normal.

Blood glucose levels were monitored from the tail vein using a True Track Smart System glucometer (Home Diagnostics, Inc., Ft. Lauderdale, FL) immediately prior to receiving STZ and at 1, 4 and 8 weeks after injection of STZ. Glucose levels of >400 mg/dl were considered the minimum blood glucose level compatible with a stable non-toxic diabetic state.12

All animals were numbered, and the investigators recording the measurements were masked to treatment.

SCHIRMER TEST

Tear secretion was measured with Schirmer strips (Alcon Laboratories, Inc., Ft. Worth TX). A standard 17 mm long Schirmer strip was inserted into the lower cul-de-sac for 1 min. The strip wetting length was measured to the nearest millimeter. Five minutes prior to administration of the Schirmer strip, animals received topical Proparacaine Hydrochloride Ophthalmic Solution 0.5% (Akorn, Inc., Buffalo Grove, IL). Testing began 1 hour after the last drop of NTX or vehicle was administered, and continued every 24 hours thereafter.

CORNEAL SENSITIVITY

Corneal sensitivity was determined by an aesthesiometer (Cochet and Bonnet-Aesthesiometer, Boca Raton, FL), with the endpoint of blinking; four measurements were taken for each animal and averaged. The values (g/mm2) were determined directly from the protocol (and conversion table) supplied by the manufacturer.

Measurements of sensitivity were conducted prior to the Schirmer test.

SLIT-LAMP OBSERVATIONS

To examine general overall morphology and pathology (e.g., corneal edema, scarring), observations with a hand-held slit lamp (Zeiss HSO 10 Hand Slit Lamp, Dublin, CA) were conducted.

TOPICAL ADMINISTRATION OF NALTREXONE

Naltrexone hydrochloride (Sigma-Aldrich, Indianapolis, IN) was prepared in Vigamox (moxifloxacin hydrochloride ophthalmic solution, Alcon, Inc, Ft. Worth, TX) at a 10−5 M concentration. NTX was given as a single drop (0.05 ml) to the central cornea of the right eye, with the lower eyelid held away from the eye to avoid overflow. NTX or vehicle was administered once at 0700 hours, or at 0700, 1100, 1400, and 1700 hours for 1 or 5 days, beginning on the 9th week after induction of diabetes.

TOPICAL ADMINISTRATION OF INSULIN

Bovine insulin (Sigma-Aldrich) was prepared in Vigamox (Alcon), and utilized at a concentration of 1 U, with a single drop administered to the central cornea of the eye according to a previous report.16. Insulin or vehicle was applied topically at 0800 hours.

DATA ANALYSIS

For body weights and glucose measurements, Student two-tailed t-tests were utilized. With Schirmer tests and aesthesiometer measurements, one-way analysis of variance with Newman-Keuls post tests was employed because measurements were conducted on a random sample of two-thirds of the rats in each group.

RESULTS

INDUCTION OF DIABETES

All rats weighed 245 ± 6 g at the time of STZ injections (Fig. 1A). Normal rats gained approximately 216 g over the course of 8 weeks. Rats in the DB group were comparable in body weight to Normal animals until 2 weeks after injection of STZ. At this time, the DB group had a 10% reduction (p<0.001) in body weight relative to Normal animals. In subsequent weeks, the DB rats weighed significantly less (approximately 17–29%) than Normal rats throughout the course of the 8-week study.

FIG. 1.

FIG. 1

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Body weights (A) and glucose levels (B) of rats rendered diabetic with STZ (Diabetic) or untreated animals receiving vehicle (Normal). (A) Body weights were recorded at the time of STZ injection (week 0), and every 2 weeks thereafter. (B) Blood glucose levels were recorded 1, 4, and 8 weeks after administration of STZ. Data are expressed as means ± SEM for 15 Normal and 25 Diabetic animals at each time point. Significantly different from Normal rats at p<0.001 (***).

Baseline glucose readings were 131 ± 8 mg/dL for all rats (Fig. 1B), and these values were maintained throughout the study in the Normal group. Rats receiving STZ became hyperglycemic within 5 days (Fig. 1B), and had glucose levels greater than 520 mg/dl throughout the duration of experimentation.

TEMPORAL COURSE OF TEAR PRODUCTION AND CORNEAL SENSITIVITY

Tear production as measured by the Schirmer test (Fig. 2A) and corneal sensitivity as determined with an aesthesiometer (Fig. 2B) in DB rats were comparable to Normal animals for the first 4 weeks after injections with STZ. Beginning on week 5, and continuing thereafter, the DB rats had a decrease of 40–47% in the Schirmer score and a 1.5–1.9-fold reduction in corneal sensitivity.

FIG. 2.

FIG. 2

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Schirmer's test (A) and corneal sensitivity (B) measured at weekly intervals after induction with STZ. (A.) Data are expressed as means ± SEM for 15 Normal and 25 Diabetic animals at each time point. Significantly different from Normal rats at p<0.05 (*), p<0.01 (**), or p<0.001 (***).

TEAR PRODUCTION AND TOPICAL NALTREXONE TREATMENT

Topical administration of 1 drop of NTX restored tear secretion to the DB rat within 1 hour (Fig. 3A). Normal and DB NTX rats had comparable Schirmer scores, whereas the DB SV rats exhibited basal tear production that was reduced by over 39% from each group. Tear production for the DB rats subjected to 1 drop of NTX was similar to Normal animals for at least 48 hours after administration. However, the DB SV rats were reduced by 29–43% from the Normal and DB NTX rats at both 24 and 48 hours.

FIG. 3.

FIG. 3

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Schirmer's test (A) and corneal sensitivity (B) of rats given 1 drop of topical NTX (DB NTX) or vehicle (DB SV), as well as untreated animals subjected to vehicle (Normal), to the cornea. Data are expressed as means ± SEM for 5–10 rats/group at each time point. Significantly different from Normal rats at p<0.05 (*), p<0.01 (**), or p<0.001 (***), and DB rats receiving NTX at p<0.05 (+), p<0.01 (++), or p<0.001 (+++).

DB rats receiving topical treatment with NTX for 1 (Fig. 4) or 5 (Fig. 5) days q.i.d. had Schirmer scores that were comparable to Normal rats beginning 1 hour after termination of drug exposure and extending for at least 3 days thereafter (Fig. 4, Fig. 5). However, the DB animals receiving sterile vehicle (i.e., DB SV group) had tear production scores that were reduced from both the Normal and the DB NTX groups by 32–53%. By 96 hours after termination of either 1 or 5 days of NTX administration (q.i.d.), the effects of NTX had attenuated so that tear production in the DB NTX group was reduced by 22–59% from Normal animals, and had similar levels of tears to the DB SV group. Measurements of the Schirmer test for the DB NTX group remained significantly reduced from the Normal animals for the duration of the experiment.

Fig. 4.

Fig. 4

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Schirmer's test (A) and corneal sensitivity (B) of rats given topical NTX (DB NTX) or vehicle (DB SV), as well as untreated animals subjected to vehicle (Normal), for 1 day (q.i.d.) to the cornea. Data are expressed as means ± SEM for 6–11 animals/group at each time point. Significantly different from Normal rats at p<0.05 (*), p<0.01 (**), or p<0.001 (***), and DB rats receiving NTX at p<0.05 (+), p<0.01 (++), or p<0.001 (+++).

Fig. 5.

Fig. 5

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Schirmer's test (A) and corneal sensitivity (B) of rats given topical NTX (DB NTX) or vehicle (DB SV), as well as untreated animals subjected to vehicle (Normal), for 5 days (q.i.d.) to the cornea. Data are expressed as means ± SEM for 5–10 rats/group at each time point. Significantly different from Normal rats at p<0.05 (*), p<0.01 (**), or p<0.001 (***), and DB rats receiving NTX at p<0.05 (+), p<0.01 (++), or p<0.001 (+++).

CORNEAL SENSITIVITY AND TOPICAL NALTREXONE TREATMENT

Topical administration of 1 drop of NTX restored corneal sensitivity to DB rats within 1 h (Fig. 3B) and extended for the entire 96 hour period of the experiment, with Normal and DB NTX rats having comparable measurements. However, the DB SV rats had a reduction in corneal sensitivity of 1.4- to 1.8-fold from the Normal and DB NTX rats over the entire 96 hour course of the study.

In contrast, DB rats receiving topical treatment with NTX for 1 or 5 days q.i.d. had corneal sensitivity scores that were comparable to Normal rats beginning 1 h after termination of drug exposure and extending for at least 4 days thereafter (Fig. 4B, Fig. 5B). However, the DB animals receiving sterile vehicle (i.e., DB SV group) had sensitivity scores that were reduced from both the Normal and the DB NTX groups by 1.5- to 2.0-fold. At 120 hours after termination of the 1 day of treatment with NTX (q.i.d.), the NTX effect had expired so that the DB NTX group of rats was reduced by 1.8-fold in sensitivity from the Normal animals, and had similar levels of sensitivity to the DB SV group. At 192 hours after termination of the 5 day treatment with NTX (q.i.d.), the DB NTX group was reduced 1.9-fold in sensitivity from the Normal animals, and had comparable values to the DB SV group. At 216 hours after termination of the 5 day regimen of NTX, the DB NTX remained 1.7-fold reduced in corneal sensitivity from the Normal animals.

NON-INVASIVE MEASUREMENTS OF CORNEAL INTEGRITY

Examination with a hand-held slit lamp during and after NTX administration did not reveal any abnormalities of the ocular surface in any animal of any group.

TEAR PRODUCTION AND CORNEAL SENSITIVITY:TOPICAL INSULIN TREATMENT

Topical administration of 1 drop of INS had no effect on tear production in DB rats (Fig. 6A). The Schirmer score for the DB INS group was decreased from Normal rats by 35–58% at the 1, 24, and 48 hour time points, whereas the DB SV group was subnormal by 27–61%. Thus, the values for the DB INS and DB SV groups were comparable.

FIG. 6.

FIG. 6

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Schirmer's test (A) and corneal sensitivity (B) of rats given 1 drop of topical insulin NTX (DB INS) or vehicle (DB SV), as well as untreated animals subjected to vehicle (Normal), to the cornea. Data are expressed as means ± SEM for 5–10 rats/group at each time point. Significantly different from Normal rats at p<0.05 (*), p<0.01 (**), or p<0.001 (***), and DB rats receiving insulin at p<0.05 (+).

Corneal sensitivity of the DB rats receiving topical INS did not differ from the Normal animals at any time point (Fig. 6B). However, the rats treated with vehicle had reductions in aesthesiometer scores ranging from 1.3- to 1.8-fold from Normal subjects, and 1.1- to 1.9-fold from the DB INS group. Corneal sensitivity for Normal and DB INS rats were comparable at 1, 24, and 48 h time points.

COMMENT

The present study makes the novel observation that topical NTX treatment in diabetic rats restores tear production, and confirms and extends previous reports17 that exposure to this opioid antagonist re-establishes corneal sensation. Inspection of the temporal course of diabetes revealed that tear production and corneal sensitivity were comparable to normal animals for at least 4 weeks after induction of the disease. However, on week 5 after the induction of diabetes, both Schirmer's test and aesthesiometer results documented the appearance of dry eye and a marked decrease in corneal sensitivity, respectively. Moreover, these abnormalities were not transient, but remained throughout the course of the experiment in untreated diabetic rats (i.e., DB SV group). Our studies reveal that treatment with even one drop of 10−5 M NTX restores both tear production and corneal sensitivity to levels similar to normal rats. This result was detected within 1 hour of NTX administration, thereby indicating an extraordinarily rapid onset of action of this opioid antagonist. The normalization of tear production and corneal sensation extended for at least 2 days after NTX treatment. Although dry eye re-appeared between 48 and 72 hours, normal corneal sensitivity remained for at least 96 hours. A more extensive treatment regimen with either 4 or 20 drops of topical NTX over a 1 or 5 day period again showed that within 1 hour of the last eye drop of NTX (10−5 M), normalization of both tear production and corneal sensitivity were recorded in diabetic animals, but in contrast to one drop of NTX, the effect lasted for at least 72 hours. As in the case of 1 drop of NTX, dry eye re-appeared considerably earlier than the loss of corneal sensation, with normal corneal sensitivity lasting at least 1 day longer with the 4 drop regimen and at least 6 days for the 20 drop regimen. Thus, to our knowledge, we have shown for the first time that treatment with topical 10−5 M NTX can normalize tear production in type 1 diabetic animals. Future studies are needed to define whether topical NTX also will be an effective treatment for dry eye in type 2 diabetes.

Both a loss of corneal sensitivity and tear production have been recorded previously in diabetic patients and animals.2,8,9 Based upon our finding that loss of corneal sensitivity and tear production had an onset at the same time in diabetic rats, and that they could be restored simultaneously, one could speculate that these two entities were interrelated. However, at least two lines of evidence in the present study suggest that corneal sensation and tear production are not entirely related. First, topical application of NTX, whether 1 drop, or for 1 or 5 days (q.i.d.), consistently revealed that dry eye reappeared at least several days prior to corneal insensitivity. Thus, if would be incorrect to postulate that restoration of tear production was due to a re-emergence of corneal sensitivity because re-establishment of corneal sensation lasted far beyond that of restoration of tear production. Second, it is known16 that topical insulin can restore corneal sensitivity in animals with type 1 diabetes, and this fact was confirmed in the present study. To test the possibility that restoration of corneal sensitivity also recovers tear production, diabetic rats were given topical insulin and received a Schirmer test. Dry eye was recorded at 1, 24, and 48 hours after administration of 1 drop of insulin, despite the fact that normal corneal sensitivity was present continuously. Therefore, at least in type 1 diabetes, corneal sensitivity does not appear to be causally related to increased tear production. These results support the findings of Inoue and colleagues7 who found that a reduced blinking rate in diabetic patients was not correlated with such ocular surface factors as corneal sensitivity, tear breakup time, or the status of the lipid layer. Moreover, Saito et al.18 have reported no correlation of corneal sensitivity with tear secretion with regard to the stage of diabetic retinopathy.

The mechanism(s) underlying dry eye and corneal insensitivity in type 1 diabetes are unknown. Some investigators have speculated that dry eye results from dysfunction of the integrated ocular surface-secretory glandular functional unit.19 This dysfunction may result from peripheral neuropathy, with disease of the sensory afferent nerves innervating the ocular surface, the autonomic (efferent) nerves innervating the tear-secreting glands, and/or the tear-secreting glands themselves.2,3,9,19–21 Additional information that inflammation, whether a cause or effect or both, frequently accompanies dry eye in rodents and humans, and may represent a potential mechanism in the etiology and pathogenesis of this disease.22,23 At least in the case of type 1 diabetes, we now have demonstrated that the causative factor(s) for both dry eye and a loss of corneal sensation are corrected within 1 hour of application of NTX. This finding implies that whatever is altering tear production and corneal sensitivity in the diabetic cornea is reversible, although it takes at least 4 weeks for the damaging influence(s) to be expressed.

Because we have used topical anesthesia prior to measuring tear production, we are not evaluating reflex response from the main lacrimal gland, but rather basal secretion from other sources such as the accessory lacrimal glands of Krause and Wolfring.24,25 These glands are said to be supplied by postganglionic, parasympathetic nerve fibers (of pterygoplataine ganglion origin) carried by the nervus intermedius from the VII cranial nerve.26–28 Given the rapid reversal of dry eye, as well as corneal insensitivity, it may be proposed that elevated opioid levels, known to occur in diabetics29,30 and which have been identified in corneal nerves,31 diminishes the responsiveness of peripheral sensory or motor nerves innervating the ocular surface and/or accessory lacrimal glands. NTX, a well-known general opioid antagonist, may be postulated to interfere with opioid-opioid receptor interactions thereby restoring tear production and corneal sensitivity. Surprisingly, even one drop of NTX may last for several days in terms of restoring function. Future studies should be directed at determining which opioid peptide(s) and receptor(s) are determinants of tear production and corneal sensation. Moreover, dry eye and a loss of corneal sensation are multifactorial disorders,32 and exploration of NTX's effectiveness in the face of diseases other than diabetes is warranted.

The present study documents reversal of dry eye and restoration of corneal sensation in diabetic animals by an opioid antagonist. It represents a paradigm shift involving the etiology, pathogenesis, and treatment of these two diabetic complications. Strategies for therapy involving interference with opioid-opioid receptor interfacing, as well as investigation into the origin and pathobiology of these complications resulting from opioid dysfunction, are warranted. Meanwhile, even one drop of NTX immediately restores corneal sensitivity and tear production in diabetic rats, and the effects can last up to 2 to 3 days. This would suggest the need for the initiation of clinical trials examining the safety and efficacy of this drug for ocular use. Moreover, it may be reasonable to evaluate the impact of NTX on other non-ocular complications of diabetes such as peripheral neuropathy, and its role, if any, in the treatment of other disorders of corneal sensitivity and/or tear production.

ACKNOWLEDGMENTS

We thank Ms. Callie Dagen for assistance with the insulin experiment.

This work was supported in part by grant EY16666 from the National Institutes of Health.

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