105

Pain, 40 (1990) 105-107 Elsevier

PAIN 01532

Effect of hyperglycemia on pain threshold in alloxan-diabetic Jana

Herrman

Lee, Daniel

Departments of Psychology and Behavioral

(Received

J. Cox, Douglas

G. Mook

Medicine and Psychiatry,

20 April 1989, revision received 1 August

and Richard

C. McCarty

University of Virginia, Chariottesvilie, 1989, accepted

24 August

rats

VA (U.S.A.)

1989)

Insulin-de~ndent diabetes mellitus (IDDM) is associated with several complications, including painful diabetic neuropathy. Both animal and human investigations suggest an altered pain response in IDDM. Furthermore, it has been suggested that glucose may be an important mediating factor in these painful symptoms. In the present study, pain threshold was assessed via tail flick latency in alloxan-diabetic and control rats. In addition, tail flick latency was determined under conditions of both hyperglycemia and euglycemia in diabetic rats. Conditions of hyperglycemia resulted in a significant decrease in the tail flick latency of alloxan-diabetic rats. In contrast, tail flick latency was significantly increased in diabetic rats following normalization of blood glucose levels. It is concluded that elevated blood glucose levels contribute to a decrease in pain threshold in alloxan-diabetic rats.

Summary

Key words: Hyperglycemia;

Euglycemia;

Pain threshold;

Diabetes;

Alloxan-diabetic

rat

Introduction

Method

Diabetes mellitus is associated with several long-term complications [3]. Prominent among these is peripheral neuropathy, often expressed as hypersensitivity to painful stimuli. A review of the published work on painful diabetic neuropathy suggests that a significant degree of neuropathic pain is more likely to occur in patients with uncontrolled diabetes [1,2,8]. It has been proposed that acute biochemical alterations in neural tissue might result from prolonged hyperglycemia and could contribute to the development of painful diabetic neuropathy [S]. In the present study, we have examined pain thresholds in alloxan-induced diabetic and control animals. We were particularly interested in comparing pain threshold levels under conditions of both hyperglycemia and euglycemia in diabetic animals.

Animals Nine female Sprague-Dawley rats were purchased from Hilltop Breeding Laboratories, Scottdale, PA. Rats were housed individually in Wahmann suspended metal cages with laboratory chow and tap water freely available. The vivarium was maintained automatically on a 12 h light-dark cycle with an ambient temperature of 21 + 1” C.

Correspondence 20: Jana Herrman Lee, Psychology Department, 102 Giimer Hall, University of Virginia, Charlottesville, VA 22903, U.S.A. 03~-3959/~/$03.50

0 1990 Elsevier Science Publishers

Ailoxan treatment Following a 48 h fast, 5 rats received intraperitoneal (i.p.) injections of alloxan monohydrate (120 mg/kg) dissolved in 0.9% sodium chloride. Four control animals received i.p. injections of 0.9% sodium chloride (2.5 ml/kg). Within 48 h following alloxan administration, blood glucose concentrations were measured via tail clip sampling. Briefly, the tip of the tail (approximately 2 mm) was clipped off using a sterile scalpel blade and 1-2 drops of blood from the cut surface were used for measurement of blood glucose with an Accu-Chek II reflectance meter (Boehringer

B.V. (Biomedical

Division)

Mannheim Diagnostics. Indianapolis, IN). Blood glucose levels were greater than 250 mg/dl in all alloxan-treated rats. Beginning on the third day after alloxan treatment, diabetic rats received daily injections of regular insulin (2 units/animal, s.c.) between 17.00 and 19.00 h for a 2 week period.

Pain threshold was measured by placing each rat’s tail in 50” C water and measuring the latency to flick. On the first day of testing, three of the diabetic animals were run under conditions of hyperglycemia and the remaining two at euglycemic values. Within 24 h, each animal was tested again in the alternate condition. Control animals were tested under euglycemic conditions only. In the hyperglycemic condition, all animals received their normal insulin dosage (2-4 units/ animat, Lilly regular insulin) at 17.00 h the evening before testing. In the euglycemic condition, insulin treatment depended on the animal’s blood glucose reading 4 h prior to testing. Insulin was administered as necessary 4 h prior to testing to ensure low blood glucose readings. The 5 test trials for each animal were spaced at 0.5 h intervals, All observations were conducted by a blind observer. Duta reduction und analysis Tail flick latencies were averaged across the 5 test trials for each animal and were used for a11 statistical tests. All data are expressed as means + S.E.M. Tail flick latencies and blood glucose were analyzed using l-way ANOVAs. Post-hoc comparisons were made using Tukey-Kramer tests [6].

Results Measures of pain threshold varied significantly across the 3 treatment groups (F (2, 11) = 16.0, P < 0.005). The tail flick Iatencies of hyperglycemic alloxan-diabetic rats (mean blood glucose > 400 mg/dI) were significantly less than those of control, non-diabetic rats (P < O.OOl), indicative of hyperalgesia. However, when these same diabetic rats were tested when blood glucose levels (BGL) were in the euglycemic range (mean BGL = 73 k 17 mg/dl), the tail flick latencies were

I,-

,i;‘l:l

:

Fig. I. Tail Rick latencies (SK) for control and hyper- and euglvcemic a~~oxan-diabetic rats. Values are presented as means and standard errors.

similar to those of control rats (see Fig. 1). Mean BGL for control rats was 96 + 7 mg/dl. Blood glucose Ievels among euglycemic alIoxan-diabetic and control animals did not differ significantly; however. hyperglycemic values for diabetic rats were significantly higher (F‘ (2, 11) = 132.X. P c 0.001).

Discussion

The present findings provide support for the idea that hyperglycemia does contribute to a state of hyperaigesia in alloxan-diabetic rats. Diabetic animals clearly demonstrated an increased sensitivity to pain when hyperglycemic. However, a normal reaction to the painful stimulus was ohserved by simply reducing BGL to euglycemic values prior to testing. Other research supports the idea that acute elevations in blood glucose may be an important mediating factor in painful diabetic neuropathy. Morley et al. [i’] demonstrated in non-diabetic subjects that a 50 g glucose infusion resulted in a decrease in pain threshold. Animal research studies are also consistent with this hypothesis. Davis et al. [4] demonstrated that elevated blood glucose ieveIs in laboratory rats reduced the response to opiate agonists and antagonists, which suggests that serum glucose levels modulate responsiveness to opiates. Contrary to this view is the idea that diabetes drastically alters secretory activity of endogenous opiate

107

systems. A recent study [5] notes that plasma, pituitary, and hypothalamic levels of the endogenous opioid peptide /3-endorphin were reduced in female rats 8 weeks following the induction of diabetes with streptozotocin. These changes in pendorphin levels were related to hyperalgesia in streptozotocin diabetic rats. Our research does not support this view. For example, if diabetes or chronic hyperglycemia does permanently alter an endogenous opiate system, one should not be able to reverse pain threshold acutely in those diabetic animals. However, the present study demonstrated that tail flick latencies of alloxan-diabetic rats were returned to control values within 24 h when blood glucose levels were normalized. In summary, the lowered pain threshold of hyperglycemic diabetic rats suggests that studies in various animal models of diabetes may serve to delineate the mechanism of this form of hyperalgesia. These results may have important clinical implications as well. If blood glucose levels are responsible in part for hyperalgesia, this measure could be used as a screening tool to guide the treatment and prevention of painful diabetic neuropathy in human diabetics.

Acknowledgements This study was supported in part by U.S. Public Health Service Grants AM282880, AM24177 and DK38942 and ADAMHA Research Scientist

Development Award MH00529 and by Training Grant HD07323. We thank Julie Landel for her assistance with data collection.

References 1 Archer, A.G., Watkins, P.J., Thomas, P.K., Sharma, A.K. and Payan, J., The natural history of acute painful diabetic neuropathy in diabetes mellitus, J. Neural. Neurosurg. Psychiat., 46 (1983) 491-499. 2 Boulton, A.J., Haristy, CA., Worthy, R.C., Drury, J., Wolf, E., Cudworth, A.G. and Ward, J., Metabolic and genetic factors in diabetic neuropathy, Diabetologia, 23 (1982) 157. 3 Cox, D.J., Gonder-Frederick, L.A., Pohl, S. and Pennebaker, J.A., Adult diabetes: critical issues in applied research and clinical intervention. In: Self-Management in Health Psychology and Behavioral Medicine, Academic Press, New York, 1986, pp. 305-346. Davis, W.M., Miya, T.S. and Edwards, L.D., The influence of glucose and insulin pretreatment upon morphine analgesia in the rat, J. Am. Pharm. Ass., 45 (1956) 60-62. Forman, L.J., Estilow, S., Lewis, M. and Vasilenko, P., Streptozotocin diabetes alters immunoreactive /3-endorphin levels and pain perception after 8 weeks in female rats, Diabetes, 35 (1986) 1309-1313. Kirk, R.E., Experimental Design: Procedures for the Behavioral Sciences, 2nd Edn., Brooks/Cole, Monterey, CA, 1982, 120 pp. Morley, G.K., Mooradian, A.D., Levine, A.S. and Morley, J.E., Mechanism of pain in diabetic peripheral neuropathy: effect of glucose on pain perception in humans, Am. J. Med., 77 (1984) 79-82. Thomas, P.K. and Eliasson, SC., Diabetic neuropathy. In: Peripheral Neuropathy, Vol. II, Saunders, Philadelphia, PA, 1984, pp. 177331810.

Effect of hyperglycemia on pain threshold in alloxan-diabetic rats.

Insulin-dependent diabetes mellitus (IDDM) is associated with several complications, including painful diabetic neuropathy. Both animal and human inve...
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