Selective T-Type Calcium Channel Blockade Alleviates Hyperalgesia in ob/ob Mice

  1. Janelle R. Latham1,
  2. Sriyani Pathirathna1,
  3. Miljen M. Jagodic1,
  4. Won Joo Choe1,2,
  5. Michaela E. Levin1,3,
  6. Michael T. Nelson1,
  7. Woo Yong Lee4,
  8. Kathiresan Krishnan5,
  9. Douglas F. Covey5,
  10. Slobodan M. Todorovic1,3,6 and
  11. Vesna Jevtovic-Todorovic1,3,6
  1. 1Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia;
  2. 2Department of Anesthesiology and Pain Medicine, InJe University, Ilsan Paik Hospital & College of Medicine, Goyang-City, Gyunggi-do, South Korea;
  3. 3Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, Virginia;
  4. 4Department of Anesthesiology and Pain Medicine, InJe University, Sanggyepaik Hospital, Seoul, South Korea;
  5. 5Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri;
  6. 6Department of Neuroscience, University of Virginia Health System, Charlottesville, Virginia.
  1. Corresponding author: Janelle Latham, jrl3c{at}virginia.edu.

Abstract

OBJECTIVE Morbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy.

RESEARCH DESIGN AND METHODS In vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice.

RESULTS We found that ob/ob mice developed significant mechanical and thermal hypersensitivity early in life that coincided with hyperglycemia and was readily reversed with insulin therapy. These disturbances were accompanied by significant biophysical and biochemical modulation of T-channels in dorsal root ganglion neurons as measured by a large increase in the amplitude of T-currents and the expression of mRNA. The most prevalent subtype, α1H (Cav3.2), was most strongly affected. Moreover, (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), a novel neuroactive steroid and selective T-channel antagonist, provided dose-dependent alleviation of neuropathic thermal and mechanical hypersensitivity in diabetic ob/ob mice.

CONCLUSIONS Our results indicate that pharmacological antagonism of T-channels is potentially an important novel therapeutic approach for the management of painful diabetic neuropathy.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received December 18, 2008.
    • Accepted July 16, 2009.
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  1. Diabetes vol. 58 no. 11 2656-2665
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