Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

Abstract

Exercise is now established as an integral adjunct to the management of diabetes. Diabetic polyneuropathy, a painful complication of diabetes, remains untreatable, emphasizing a critical need for improved therapeutic strategies. Recent evidence suggests that exercise may facilitate recovery of peripheral nerve function in diabetes. However, the mechanism by which exercise protects against diabetes-induced nerve dysfunction is unknown. In this dissertation we hypothesized that forced-exercise protects against experimental DPN by preventing glucose-associated alterations of voltage-gated calcium currents (VGCC) in small diameter dorsal root ganglion (DRG) neurons. Using behavioral, nerve-electrophysiology and patch-clamp methodology we examined the functional consequences of forced-exercise (treadmill, 5.4 km/week) on VGCC in dissociated small diameter DRG neurons from rats conferred diabetic by streptozotocin (STZ) treatment. Exercised-STZ rats in comparison to sedentary-STZ rats, demonstrated a 4 week delay in the onset of tactile hyperalgesia that was independent of changes in blood glucose levels. Interestingly, forced-exercise induced protection against diabetes-induced tactile hyperalgesia was reversed in a dose dependent manner by the opioid antagonist, naloxone. Forced-Exercise also prevented peripheral nerve conduction deficits in STZ-treated rats. Small diameter DRG neurons harvested from sedentary-STZ rats with demonstrated hyperalgesia exhibited 2-fold increase in peak high-voltage activated (HVA) Ca2+ current density and low-voltage activated (LVA) Ca2+ current component. The steady-state inactivation (SSI) (measure of channel availability) of LVA currents demonstrated a rightward shift in sedentary-STZ rats (+7.5 mV shift; V50 = -50.9 ± 0.6 mV; vehicle treated rats V50 = -58.4 ± 0.9 mV). Forced-exercise prevented the increase in both, peak HVA Ca2+ current density and LVA SSI shift (V50 = -58.2 ± 1.4 mV), but did not alter LVA current component. We conclude that forced-exercise delayed the onset of diabetic tactile hyperalgesia by preventing the alteration of VGCCs in small diameter DRG neurons, possibly by decreasing total calcium influx and dampening neuronal over-excitability.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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