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The Journal of Neuroscience, March 21, 2007, 27(12):3305-3316; doi:10.1523/JNEUROSCI.4866-06.2007

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Cellular/Molecular
Cell-Specific Alterations of T-Type Calcium Current in Painful Diabetic Neuropathy Enhance Excitability of Sensory Neurons

Miljen M. Jagodic,¹ Sriyani Pathirathna,¹ Michael T. Nelson,^1,4 Stefani Mancuso,¹ Pavle M. Joksovic,¹ Ethan R. Rosenberg,¹ Douglas A. Bayliss,^1,3,4 Vesna Jevtovic-Todorovic,^1,2,4 and Slobodan M. Todorovic^1,2,4

¹Departments of Anesthesiology, ²Neuroscience, and ³Pharmacology and ⁴Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, Virginia 22908

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908-0710. Email: st9d{at}virginia.edu

Recent data indicate that T-type Ca²⁺ channels are amplifiers of peripheral pain signals, but their involvement in disorders of sensory neurons such as those associated with diabetes is poorly understood. To address this issue, we used a combination of behavioral, immunohistological, molecular, and electrophysiological studies in rats with streptozotocin (N-[methylnitrosocarbamoil]-D-glucosamine)-induced early diabetic neuropathy. We found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L₄–L₅ dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation. This not only correlated closely with more prominent afterdepolarizing potentials (ADPs) but also increased cellular excitability manifested as a lower threshold for burst firing in diabetic than in control cells. T-type currents and ADPs were potently inhibited by nickel and enhanced by L-cysteine, suggesting that the Ca_V3.2 T-type channel isoform was upregulated. Both control and diabetic DRG cells with ADPs stained positively for isolectin B₄, but only diabetic cells responded robustly to capsaicin, suggesting enhanced nociceptive function. Because increased excitability of sensory neurons may result in such pathological perceptions of pain as hyperalgesia and allodynia, upregulation of T-type Ca²⁺ currents and enhanced Ca²⁺ entry into these cells could contribute to the development of symptoms in diabetic neuropathy.

Key words: low-threshold calcium channel; calcium; dorsal root ganglion; capsaicin; pain; diabetes

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Received Nov. 8, 2006; revised Jan. 22, 2007; accepted Feb. 15, 2007.

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908-0710. Email: st9d{at}virginia.edu

This article has been cited by other articles:

				J. R. Latham, S. Pathirathna, M. M. Jagodic, W. Joo Choe, M. E. Levin, M. T. Nelson, W. Yong Lee, K. Krishnan, D. F. Covey, S. M. Todorovic, et al. Selective T-Type Calcium Channel Blockade Alleviates Hyperalgesia in ob/ob Mice Diabetes, November 1, 2009; 58(11): 2656 - 2665. [Abstract] [Full Text] [PDF]

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