Elsevier

Neurobiology of Disease

Volume 24, Issue 2, November 2006, Pages 384-394
Neurobiology of Disease

Mechanical hyperalgesia correlates with insulin deficiency in normoglycemic streptozotocin-treated rats

https://doi.org/10.1016/j.nbd.2006.07.009Get rights and content

Abstract

The triggers and pathogenesis of peripheral diabetic neuropathy are poorly understood, and this study evaluated the role of insulinopenia in nociceptive abnormalities in the streptozotocin (STZ) rat model of diabetes to test the hypothesis that, in addition to hyperglycemia, impairment of insulin signaling may be involved in progression of neuropathy. We measured blood glucose, plasma insulin, and sciatic nerve glucose and sorbitol levels, and withdrawal thresholds for hind limb pressure pain and heat pain in STZ-injected rats that developed hyperglycemia or remained normoglycemic. The pressure pain threshold did not change in vehicle-injected controls, but during the 2 weeks after STZ, it decreased by 25–40% in STZ-hyperglycemic and STZ-normoglycemic animals (P < 0.05). Mean heat pain threshold did not change in STZ-normoglycemic rats, but increased by about 1.5°C in STZ-hyperglycemic rats (P < 0.05). These pain thresholds did not correlate with blood or nerve glucose or sorbitol levels, but both correlated with plasma insulin level in STZ-normoglycemic rats, and low-dose insulin replacement normalized the pressure threshold without affecting blood glucose level. Thus, at least one of early signs of diabetic neuropathy in STZ-treated rats, mechanical hyperalgesia, can be triggered by moderate insulinopenia, irrespective of glycemic status of the animals.

Introduction

Chronic, systemic hyperglycemia has been historically viewed as a major trigger for the pathogenic mechanisms of neurologic complications of type I and type II diabetes (Ishii, 1995, Sugimoto et al., 2000a). For example, distal peripheral neuropathy is a frequent symptom of diabetes, and most symptoms of this neuropathy may be explained as either immediate or secondary consequences of hyperglycemia-associated activation of aldose reductase (the first enzyme in polyol pathway), which causes nerve sorbitol accumulation followed by osmotic, metabolic, oxidative and circulatory imbalance in peripheral nervous tissue (Sugimoto et al., 2000a). Further support for the hyperglycemic hypothesis comes from clinical trials showing that stringent glycemic control decreases the incidence of peripheral neuropathy by as much as 60% to 70% over several years (Boulton et al., 2004, DCCT, 1993), and from animal research demonstrating parallel development of hyperglycemia, nerve conduction slowing, and nociceptive impairments and an apparent association between hyperglycemia, sensitivity of cutaneous nociceptors, and mechanical hyperalgesia (Biessels et al., 1999, Dobretsov et al., 2001, Dobretsov et al., 2003, Khan et al., 2002, Sugimoto et al., 2000a, Suzuki et al., 2002).

In spite of persuasive supporting evidence, the glucose hypothesis alone does not fully explain the variety and complexity of clinical presentations of distal peripheral neuropathy. While glucose control is an effective preventive measure, during 5 years of follow up study at least 30% of diabetic patients with apparently satisfactory control of blood glucose level still developed neuropathy (DCCT, 1993). Furthermore, there is a high incidence of painful neuropathies in pre-diabetic patients who have impaired glucose tolerance but are normoglycemic or moderately hyperglycemic (Singleton et al., 2001). Moreover, neither clinical (Chan et al., 1990, Thye-Ronn et al., 1994) nor animal (Courteix et al., 1996, Dobretsov et al., 2003, Maneuf et al., 2004, Romanovsky et al., 2004) studies have shown a correlation between hyperglycemic status and pain/hyperalgesia. Taken together, these observations suggest that factors in addition to hyperglycemia must play a role in the pathogenesis of distal peripheral neuropathy, and identification and evaluation of the causative mechanisms of peripheral neuropathy are important, not only for understanding the clinical course of the disorder, but also for the development of new strategies for its treatment and prevention.

Recent data from several independent laboratories implicate insulinopenia as a contributory factor in development of peripheral neuropathy (Brussee et al., 2004, Huang et al., 2003, Schmidt et al., 2004), and our initial studies suggest that mechanical hyperalgesia, a symptom of distal peripheral neuropathy, is caused by insulinopenia without accompanying hyperglycemia in a rat model using the pancreatic toxin streptozotocin (STZ) (Romanovsky et al., 2004). Establishing a neuropathic role for insufficiency of insulin signaling may help explain the apparent inconsistencies related to the glucose dependence of the origin of pain, especially in pre-diabetic patients, and the present study was, therefore, designed to examine relationships among insulinopenia, hyperglycemia, and early signs of neuropathy reflected by abnormalities of nociception in STZ-treated rats.

Section snippets

Materials and Methods

All experimental procedures followed “Principles of laboratory animal care” (NIH publication no. 85-23, revised 1985) and were reviewed and approved by the Institutional Animal Care and Use Committee.

Temporal progression of weight loss, blood glucose, and altered pain thresholds

Out of 18 rats injected with STZ in the first group of rats, 61% developed overt hyperglycemia by day 3 (STZ-hyperglycemic) and exhibited progressive weight loss thereafter (Figs. 1A, B); these animals became less sensitive to higher temperatures within 4 days (increased heat pain threshold [HPT], Fig. 1C) and less tolerant to pressure applied to the paw (decreased pressure pain threshold [PPT], Fig. 1D). All these changes were statistically significant in comparison to their within-group

Discussion

The two major findings of the present study are that nociceptive pressure thresholds in STZ-normoglycemic rats correlate with the level of circulating insulin and low-dose insulin replacement therapy corrects both insulinopenia and the deficiency of pressure pain threshold without modulation of blood glucose level. Distal peripheral neuropathy is one of most frequent and troublesome complications of diabetes mellitus (Boulton et al., 2004), and our observations are relevant to three questions

Acknowledgments

This work was supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases (DK067248 to MD) and National Institute of Neurological Disorders and Stroke (NS036728 to GD).

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