Ryu Sang Wan, Kim Yeo Ok, Kim Han-Byul, Oh Seog Bae, Choi Jeong Il, Yoon Myung Ha
Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, Gwangju, Republic of Korea.
Department of Neurobiology and Physiology, School of Dentistry Seoul National University, Seoul, Republic of Korea; Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Eur J Pharmacol. 2021 May 15;899:174029. doi: 10.1016/j.ejphar.2021.174029. Epub 2021 Mar 13.
The recently identified molecule P7C3 has been highlighted in the field of pain research. We examined the effect of intrathecal P7C3 in tissue injury pain evoked by formalin injection and determined the role of the GABA system in the activity of P7C3 at the spinal level. Male Sprague-Dawley rats with intrathecal catheters implanted for experimental drug delivery were studied. The effects of intrathecal P7C3 and nicotinamide phosphoribosyltransferase (NAMPT) administered 10 min before the formalin injection were examined. Animals were pretreated with bicuculline, a GABA-A receptor antagonist; saclofen, a GABA-B receptor antagonist; L-allylglycine, a glutamic acid decarboxylase (GAD) blocker; and CHS 828, an NAMPT inhibitor; to observe involvement in the effects of P7C3. The effects of P7C3 alone and the mixture of P7C3 with GABA receptor antagonists on KCl-induced calcium transients were examined in rat dorsal root ganglion (DRG) neurons. The expression of GAD and the concentration of GABA in the spinal cord were evaluated. Intrathecal P7C3 and NAMPT produced an antinociceptive effect in the formalin test. Intrathecal bicuculline, saclofen, L-allylglycine, and CHS 828 reversed the antinociception of P7C3 in both phases. P7C3 decreased the KCl-induced calcium transients in DRG neurons. Both bicuculline and saclofen reversed the blocking effect of P7C3. The levels of GAD expression and GABA concentration decreased after formalin injection and were increased by P7C3. These results suggest that P7C3 increases GAD activity and then increases the GABA concentration in the spinal cord, which in turn may act on GABA receptors causing the antinociceptive effect against pain evoked by formalin injection.
最近发现的分子P7C3在疼痛研究领域受到了关注。我们研究了鞘内注射P7C3对福尔马林注射诱发的组织损伤性疼痛的影响，并确定了GABA系统在脊髓水平P7C3活性中的作用。对植入鞘内导管用于实验性药物递送的雄性Sprague-Dawley大鼠进行了研究。检测了在福尔马林注射前10分钟鞘内注射P7C3和烟酰胺磷酸核糖转移酶（NAMPT）的效果。动物分别用GABA-A受体拮抗剂荷包牡丹碱、GABA-B受体拮抗剂氯苯氨丁酸、谷氨酸脱羧酶（GAD）阻滞剂L-烯丙基甘氨酸和NAMPT抑制剂CHS 828进行预处理，以观察它们对P7C3作用的影响。在大鼠背根神经节（DRG）神经元中检测了单独使用P7C3以及P7C3与GABA受体拮抗剂混合物对氯化钾诱导的钙瞬变的影响。评估了脊髓中GAD的表达和GABA的浓度。鞘内注射P7C3和NAMPT在福尔马林试验中产生了镇痛作用。鞘内注射荷包牡丹碱、氯苯氨丁酸、L-烯丙基甘氨酸和CHS 828在两个阶段均逆转了P7C3的镇痛作用。P7C3降低了DRG神经元中氯化钾诱导的钙瞬变。荷包牡丹碱和氯苯氨丁酸均逆转了P7C3的阻断作用。福尔马林注射后GAD表达水平和GABA浓度降低，而P7C3使其升高。这些结果表明，P7C3增加GAD活性，进而增加脊髓中GABA的浓度，这反过来可能作用于GABA受体，对福尔马林注射诱发的疼痛产生镇痛作用。
