Inhibitory action of protein kinase Cbeta inhibitor on tetrodotoxin-resistant Na+ current in small dorsal root ganglion neurons in diabetic rats

Fumiko Hayase, Hiroshi Matsuura, Mitsuru Sanada, Kanako Kitada-Hamada, Mariko Omatsu-Kanbe, Kengo Maeda, Atsunori Kashiwagi, Hitoshi Yasuda
Neuroscience Letters 2007 April 24, 417 (1): 90-4
Experimental evidence has been presented to suggest that protein kinase Cbeta isoform-selective inhibitor LY333531 is effective at alleviating diabetic hyperalgesia. In the present study, we isolated small (< or =25 microm in soma diameter) dorsal root ganglion (DRG) neurons from control and streptozocin (STZ)-induced diabetic rats, and examined the acute action of LY333531 (1-1000 nM) on the tetrodotoxin-resistant Na(+) current (TTX-R I(Na)), which plays an essential role in transmitting nociceptive impulses, using the whole-cell patch-clamp method. TTX-R I(Na) in diabetic DRG neurons was enhanced in amplitude (71.5+/-3.6pA/pF, n=10 versus 41.2+/-3.3pA/pF, n=8) and was activated at more negative potentials (V(1/2), -15.1+/-1.3 mV versus -9.6+/-1.4 mV), compared with that in control neurons. Bath application of LY333531 acutely inhibited TTX-R I(Na) in both control and diabetic DRG neurons, and the degree of inhibition by the drug at concentrations of 1, 10 and 100 nM was significantly greater in diabetic DRG neurons than in control DRG neurons. Thus, TTX-R I(Na), which is upregulated in the diabetic state, is likely to be more potently inhibited by submicromolar concentrations of LY333531. These results suggest that an acute inhibition of TTX-R I(Na) by LY333531 attenuates the exaggerated excitability of DRG neurons in the diabetic state, which appears to be related at least partly to anti-hyperalgesic actions of the drug in diabetic neuropathy.

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