Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice

Abstract

The quantification of epidermal innervation, which consists primarily of heat-sensitive C-fibers, is emerging as a tool for diagnosing and staging diabetic neuropathy. However, the relationship between changes in heat sensitivity and changes in epidermal innervation has not yet been adequately explored. Therefore, we assessed epidermal nerve fiber density and thermal withdrawal latency in the hind paw of Swiss Webster mice after two and four weeks of streptozotocin-induced diabetes. Thermal hypoalgesia developed after only two weeks of diabetes, but a measurable reduction in PGP9.5-immunoreactive epidermal nerve fiber density did not appear until four weeks. These data suggest that impaired epidermal nociceptor function contributes to early diabetes-induced thermal hypoalgesia prior to the loss of peripheral terminals.Keywords diabetic neuropathy; epidermal nerve fiber density; GAP-43; PGP9.5; substance P; thermal hypoalgesia Nearly half of all diabetic patients will develop some form of peripheral neuropathy, with distal symmetric polyneuropathy the most common form [24,33]. Depletion of intra-epidermal nerve fibers (IENFs), representing the peripheral terminals of nociceptive unmyelinated C-fibers, appears to be an early index of diabetic neuropathy [30]. Resulting sensory disorders in diabetic patients range from hyperalgesia and allodynia to progressive hypoalgesia that, in conjunction with microvascular disease and impaired wound healing, leaves limbs vulnerable to infections and amputation.Diabetes-induced reductions in epidermal innervation have been observed in multiple clinical studies, as well as in diabetic primates and rodents [for review see 1,17 and references therein]. IENF loss has been correlated with measures of nerve function to assess its predictive value for other aspects of diabetic neuropathy. In humans, reductions in IENF density have been correlated with changes in pressure and vibration perception, total neurological disability score and neuropathy status [25,31]. In rats, IENF loss correlates with changes in caudal sensory nerve conduction velocity [16].One would logically predict that loss of thermal sensation is a consequence of diminished epidermal innervation. Indeed, reductions in IENF density induced by topical application of Correspondence to: Andrew P. Mizisin, Ph.D., Department of Pathology 0612, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla CA 92093-0612, Tel: (858) 822-3894, FAX: (858) 534-1886, email: amizisin@ucsd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. capsaicin to the skin ...

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

“…However, the absence of a simple linear association between IENF density and thermal sensitivity has been noted previously (23,42). This phenomenon may reflect the specificity of sensory neuron subpopulations for heat sensation and growth factors (43) and/or a step function between IENF loss and behavioral response to noxious thermal stimuli (44).…”

“…These findings imply that XIB4035 or related molecules could provide a new strategy for SFN treatment with potentially lower risk for side effects because of the topical delivery route and their limited signaling effects. (22) and in animal models of SFN (23). Interestingly, line-D SFN correlates with a significant reduction of GDNF protein in peripheral nerves (7).…”

“…We chose the streptozotocin (STZ)-induced diabetes model, in which STZ-induced pancreatic beta cell death causes diabetes (24) and produces SFN symptoms, including loss of thermal sensation (23). We initiated treatment early in the disease, i.e., after mice became hyperglycemic (>15 mmol/L) and continued it for 16 wk.…”

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…Thermal hypoalgesia was shown to develop prior to small sensory nerve fiber degeneration in STZ-diabetic C57Bl/6J mice, 46 an observation later reproduced in the STZ-diabetic Swiss Webster mouse model. 49 Zucker diabetic fatty rats displayed intraepidermal nerve fiber loss in the absence of thermal hypoalgesia. 60 Furthermore, a peroxynitrite decomposition catalyst treatment alleviated thermal hypoalgesia, but not intraepidermal nerve fiber loss, in ob/ob mice.…”

Mouse models of diabetic neuropathy

“…These models accurately mimic the metabolic phenotype of T1DM and develop DPN; however, these models do not reflect the severity of human DPN and display only mild neurophysiologic deficits (Beiswenger et al 2008;Li et al 2005;Sullivan et al 2007;Wright and Nukada 1994). An overview of these models, including available DPN phenotype data, is discussed below and summarized in Table 1.…”