Messinger Richard B, Naik Ajit K, Jagodic Miljen M, Nelson Michael T, Lee Woo Yong, Choe Won Joo, Orestes Peihan, Latham Janelle R, Todorovic Slobodan M, Jevtovic-Todorovic Vesna
Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, VA 22908, USA.
Pain. 2009 Sep;145(1-2):184-95. doi: 10.1016/j.pain.2009.06.012. Epub 2009 Jul 3.
Earlier, we showed that streptozocin (STZ)-induced type 1 diabetes in rats leads to the development of painful peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia and mechanical allodynia accompanied by significant enhancement of T-type calcium currents (T-currents) and cellular excitability in medium-sized dorsal root ganglion (DRG) neurons. Here, we studied the in vivo and in vitro effects of gene-silencing therapy specific for the Ca(V)3.2 isoform of T-channels, on thermal and mechanical hypersensitivities, and T-current expression in small- and medium-sized DRG neurons of STZ-treated rats. We found that silencing of the T-channel Ca(V)3.2 isoform using antisense oligonucleotides, had a profound and selective anti-hyperalgesic effect in diabetic rats and is accompanied by significant down-regulation of T-currents in DRG neurons. Anti-hyperalgesic effects of Ca(V)3.2 antisense oligonucleotides in diabetic rats were similar in models of rapid and slow onset of hyperglycemia following intravenous and intraperitoneal injections of STZ, respectively. Furthermore, treatments of diabetic rats with daily insulin injections reversed T-current alterations in DRG neurons in parallel with reversal of thermal and mechanical hypersensitivities in vivo. This confirms that Ca(V)3.2 T-channels, important signal amplifiers in peripheral sensory neurons, may contribute to the cellular hyperexcitability that ultimately leads to the development of painful PDN.
此前，我们发现链脲佐菌素（STZ）诱导的大鼠1型糖尿病会导致疼痛性外周糖尿病神经病变（PDN）的发展，表现为热痛觉过敏和机械性异常性疼痛，同时伴有中型背根神经节（DRG）神经元中T型钙电流（T电流）和细胞兴奋性的显著增强。在此，我们研究了针对T通道Ca（V）3.2亚型的基因沉默疗法对STZ处理大鼠的小型和中型DRG神经元的热和机械超敏反应以及T电流表达的体内和体外影响。我们发现，使用反义寡核苷酸沉默T通道Ca（V）3.2亚型，在糖尿病大鼠中具有深刻且选择性的抗痛觉过敏作用，并伴有DRG神经元中T电流的显著下调。Ca（V）3.2反义寡核苷酸在糖尿病大鼠中的抗痛觉过敏作用，在分别经静脉和腹腔注射STZ后快速和缓慢发生高血糖的模型中相似。此外，每日注射胰岛素治疗糖尿病大鼠可逆转DRG神经元中的T电流改变，同时在体内逆转热和机械超敏反应。这证实了Ca（V）3.2 T通道作为外周感觉神经元中的重要信号放大器，可能导致细胞过度兴奋，最终导致疼痛性PDN的发展。
