Inhibition of the tetrodotoxin(TTX)-resistant Na⁺ current by the protein kinase C beta inhibitor LY333531 in small dorsal root ganglion (DRG) neurons of diabetic rats

Abstract

The protein kinase Cβ inhibitor LY333531 has been shown to be effective at alleviating diabetic hyperalgesia in experimental animals. However, it still remains unknown as to whether LY333531 affects the excitability of small dorsal root ganglion (DRG) neurons, which primarily transmit nociceptive information. The present study was undertaken to examine the effect of LY333531 on the tetrodotoxin (TTX)-resistant Na+ current in small (≤25 μm in soma diameter) DRG neurons in streptozocin (STZ)-induced diabetic rats, using the whole-cell patch-clamp method. The cell membrane was initially hyperpolarized from a holding potential of -70 mV to -120 mV for 20ms and then depolarized to various test potentials ranging from -50 to +40 mV, in the presence of TTX (0.1 μM) and the appropriate blockers for Ca²⁺ and K⁺ currents. The TTX-resistant Na+ current, identified as a transient inward current during depolarization, peaked at a test potential of 0 mV and its maximal density was 44.2±12.6 pA/pF (n = 8). Bath application of LY333531 (≥0.1 μM) acutely inhibited the TTX-resistant Na+ current, which was partially reversed upon washout of the drug. Maximal effect (34.8±5.5% inhibition, n = 8) was obtained with 1 μM LY333531. Thus, LY333531 substantially inhibits the TTX-resistant Na⁺+current in diabetic rats, which appears to mediate at least partly the anti-hyperalgesic actions of LY333531 in diabetes. [Jpn J Physiol 55 Suppl:S126 (2005)]