Forced-Exercise Alleviates Neuropathic Pain in Experimental Diabetes: Effects on Voltage-Gated Calcium Channels

<p>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) Ca<super>2+</super> current density and low-voltage activated (LVA) Ca<super>2+</super> 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 Ca<super>2+</super> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Year dc:date.available

2010

Author dc:creator

• Shankarappa, Sahadev A.

• Calcium
• Diabetes
• Exercise
• Hyperalgesia
• Neuropathy
• Pain
• Neuroscience and Neurobiology

Repository record dc:identifier

https://ecommons.luc.edu/luc_diss/187

OAI identifier oai:identifier

oai:ecommons.luc.edu:luc_diss-1186