Elsevier

Neuroscience

Volume 102, Issue 1, 2 January 2001, Pages 185-192
Neuroscience

Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat

https://doi.org/10.1016/S0306-4522(00)00454-1Get rights and content

Abstract

While clinical characteristics of diabetic painful neuropathy are well described, the underlying electrophysiological basis of the exaggerated painful response to stimuli, as well as the presence of spontaneous pain, are poorly understood. In order to elucidate peripheral contributions to painful diabetic neuropathy, we quantitatively evaluated the function of C-fibers in a rat model of painful diabetic neuropathy, diabetes induced by the pancreatic β-cell toxin streptozotocin. While there was no significant effect of diabetes on conduction velocity, mechanical threshold or spontaneous activity, the number of action potentials in response to sustained threshold and suprathreshold mechanical stimuli was significantly increased in the diabetic rats. Moreover, there was a clustering of responses of C-fibers in diabetic rats; while two-thirds of C-fibers fired at the same mean frequency as C-fibers in control rats, one-third of C-fibers in diabetic rats were markedly hyper-responsive, demonstrating a threefold increase in firing frequency. The high-firing-frequency C-fibers in rats with diabetes also had faster conduction velocity than the low-firing-frequency C-fibers in rats with diabetes or in C-fibers in control rats. The hyper-responsiveness was characterized by a selective increase of the shortest interspike intervals (<100 ms) in the burst component (first 10 s) of the response to a sustained suprathreshold stimulus; in the plateau phase (last 50 s) of the response to a 60-s suprathreshold stimulus, we found a selective increase of interspike intervals between 100 and 300 ms in hyper-responsive C-fibers in rats with diabetes. The hyper-responsiveness did not correlate with mechanical threshold, presence of spontaneous activity or location of the fiber’s receptive field.

In summary, in an established model of painful diabetic neuropathy in the rat, a subset of C-fibers demonstrated a marked hyper-responsiveness to mechanical stimuli. The subset was also found to have a greater mean conduction velocity than the fibers not demonstrating this hyper-responsivity. The present findings suggest that study of individual neurons in vitro may allow elucidation of the ionic basis of enhanced nociception in diabetic neuropathy.

Section snippets

Animal model

Sprague–Dawley rats (280–320 g) from Bantin & Kingman (Fremont, CA, USA) were injected with STZ (70 mg/kg, s.c.; Sigma, St Louis, MO, USA). The onset of the diabetic state appeared one to three days after injection of STZ, as assessed by the presence of increased glucose (>500 mg/dl; Keto-Diastix®, Bayer) and ketone (>40 mg/dl; Keto-Diastix®, Bayer) in the rat’s urine. The diabetic rats were housed individually on deep wood-chip bedding, and provided with 0.45% saline for drinking and standard rat

General characteristics of C-fibers that are unchanged in diabetes

The location of receptive fields of C-fibers from control and diabetic rats was similar. In the absence of stimulation, most of the C-fibers studied from control (91%) and diabetic (85%) rats had no ongoing activity; the few fibers that did fired at less than 0.04 Hz. The mean values of conduction velocities from control and diabetic rats were 0.89±0.07 and 0.88±0.04 m/s, respectively (P>0.05; Fig. 1A). The distribution of the mechanical thresholds for C-fibers from diabetic and control rats was

Discussion

While the mechanical threshold of C-fibers in STZ-diabetic rats was not significantly different from that of C-fibers in control rats, sustained mechanical stimulation elicited significantly more action potentials in C-fibers in diabetic rats. This finding is similar to what has been observed in the vincristine model of chemotherapy-induced painful neuropathy26 and in a model of traumatic neuropathy.21 Since all C-fibers do not have the same threshold, the finding of no change in C-fiber

Conclusions

We describe alterations in C-fiber responsivity detectable in a model of painful diabetic neuropathy, which suggest that changes in a subset of nociceptors may contribute to the enhanced nociception seen in painful diabetic neuropathy.

Acknowledgements

This research was supported by NIH grant DE08973. We would like to thank Drs David Reichling and Phillip Heller for helpful comments on the manuscript, and Drs Sachia Khasar and Dennis Mendoza for assistance with the rat model of diabetic neuropathy.

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