Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

  1. Hyoh Kim1,
  2. Teiji Sasaki1,
  3. Kengo Maeda1,
  4. Daisuke Koya2,
  5. Atsunori Kashiwagi3 and
  6. Hitoshi Yasuda1
  1. 1Division of Neurology, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
  2. 2Division of Nephrology and Diabetes, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
  3. 3Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
  1. Address correspondence and reprint requests to Hitoshi Yasuda, PhD, Division of Neurology, Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan. E-mail: hyasuda{at}belle.shiga-med.ac.jp

Abstract

Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKCβ inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKCβ-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKCβ and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.

Footnotes

    • Accepted May 1, 2003.
    • Received August 20, 2002.
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