Pabbidi Mallikarjuna R, Premkumar Louis S
Department of Pharmacology, University of Mississippi Medical Center, Jackson, USA.
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
J Diabetes Treat. 2017;2017(4). Epub 2017 Oct 17.
1.1.Transient Receptor Potential (Vanilloid 1) TRPV1 and (Melastatin 8) TRPM8 are heat and cold sensing non-selective cation channels, respectively. We sought to correlate the modulation of TRPV1- and TRPM8-mediated membrane currents and altered thermal sensitivity in Diabetic Peripheral Neuropathy (DPN).
1.2.Streptozotocin (STZ)-induced diabetic mice were used and thermal (heat and cold) pain sensitivities were determined using hot plate and acetone drop test, respectively. Membrane currents were recorded using patch-clamp techniques.
1.3.First, we tested thermal pain sensitivities to implicate a possible role of TRPV1 and TRPM8 in DPN. Paw withdrawal latency on a hot plate test was decreased, and acetone-induced cold sensitivity was enhanced in diabetic mice as compared to non-diabetic mice. Dorsal Root Ganglion (DRG) neurons dissociated from diabetic hyperalgesic mice exhibited an increase in TRPV1-mediated current and a decrease in TRPM8-mediated currents as compared to non-diabetic mice. Then, we determined the modulation of TRPV1- and TRPM8-mediated currents using HEK cells heterologously expressing TRPV1 by promoting PKC- and PKA-mediated phosphorylation. Both Phorbol 12,13-Dibutyrate (PDBu), a PKC activator and forskolin, a PKA activator upregulated TRPV1-mediated currents but downregulated TRPM8-mediated currents. In diabetic mice, intraplantar injection of capsaicin, a TRPV1 agonist-induced nocifensive behavior but the severity of this behavior was significantly lower when co-administered with menthol, a TRPM8 agonist.
1.4.These findings suggest that diabetic thermal hyperalgesia mediated by up-regulation of TRPV1 function may be further aggravated by the downregulation of TRPM8 function. Targeting TRPV1 may be a useful approach to alleviate pain associated with DPN.
1.1. 瞬时受体电位香草酸亚型1（TRPV1）和褪黑素8型（TRPM8）分别是热觉和冷觉感应的非选择性阳离子通道。我们试图关联TRPV1和TRPM8介导的膜电流调节与糖尿病性周围神经病变（DPN）中热敏感性的改变。
1.2. 使用链脲佐菌素（STZ）诱导的糖尿病小鼠，分别通过热板法和丙酮滴注试验测定热（热和冷）痛敏感性。采用膜片钳技术记录膜电流。
1.3. 首先，我们测试了热痛敏感性，以探究TRPV1和TRPM8在DPN中可能的作用。与非糖尿病小鼠相比，糖尿病小鼠在热板试验中的爪部撤离潜伏期缩短，丙酮诱导的冷敏感性增强。与非糖尿病小鼠相比，从糖尿病性痛觉过敏小鼠分离出的背根神经节（DRG）神经元表现出TRPV1介导的电流增加和TRPM8介导的电流减少。然后，我们通过促进蛋白激酶C（PKC）和蛋白激酶A（PKA）介导的磷酸化，使用异源表达TRPV1的人胚肾（HEK）细胞来确定TRPV1和TRPM8介导电流的调节。PKC激活剂佛波醇12,13 - 二丁酸酯（PDBu）和PKA激活剂福斯高林均上调TRPV1介导的电流，但下调TRPM8介导的电流。在糖尿病小鼠中，足底注射TRPV1激动剂辣椒素会诱发伤害性反应，但与TRPM8激动剂薄荷醇共同给药时，这种反应的严重程度明显降低。
1.4. 这些发现表明，由TRPV1功能上调介导的糖尿病性热痛觉过敏可能会因TRPM8功能下调而进一步加重。靶向TRPV1可能是缓解与DPN相关疼痛的一种有效方法。
