Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China, and Department of Life Science, Fudan University, Shanghai 200433, China.
J Neurosci. 2014 Jan 8;34(2):346-55. doi: 10.1523/JNEUROSCI.3160-13.2014.
SIP30 (SNAP25 interacting protein of 30) is a SNAP25 interaction protein of 30 kDa that functions in neurotransmitter release. Using a chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord and brain and identified sip30, which was upregulated after CCI. Here, we show that CCI induced a bilateral increase of SIP30 in the rostral anterior cingulate cortex (rACC), a key brain region that has been implicated in pain affect. We put rats in a chamber with one half painted white (light area) and the other half painted black (dark area), and measured neuropathic pain-evoked place escape/avoidance paradigm (PEAP) to quantify the level of negative emotion evoked by painful stimuli using a Von Frey hair. Inhibition of CCI-mediated induction of SIP30 by intra-rACC injection of shRNA targeting the rat sip30 gene reduced PEAP. Interestingly, knockdown of SIP30 did not affect CCI-induced evoked pain such as heat hyperalgesia and mechanical allodynia. Neither did it affect general learning and memory. CCI-induced upregulation of SIP30 was correlated with activation of ERK, PKA, and CREB in the rACC. Intra-rACC administration of PKA or ERK inhibitors suppressed CCI-induced SIP30 upregulation and blocked the induction of PEAP. Additionally, knockdown of SIP30 suppressed the frequency of mEPSCs and increased paired-pulse ratios in rACC slices and decreased extracellular glutamate concentrations. Together, our results highlight SIP30 as a target of PKA and ERK in the rACC to mediate neuropathic pain-evoked negative emotion via modulation of glutamate release and excitatory synaptic transmission.
SIP30（突触融合蛋白 25 相互作用蛋白 30）是一种 30kDa 的突触融合蛋白 25 相互作用蛋白，在神经递质释放中起作用。使用神经病理性疼痛的慢性缩窄性损伤（CCI）模型，我们对大鼠脊髓和大脑中的基因表达进行了分析，鉴定出 sip30，CCI 后其表达上调。在这里，我们显示 CCI 诱导 SIP30 在额前扣带皮层（rACC）的双侧增加，rACC 是一个与疼痛情感有关的关键脑区。我们将大鼠放入一个有一半涂成白色（亮区）和另一半涂成黑色（暗区）的室中，并用 Von Frey 毛发测量神经病理性疼痛诱发的位置逃避/回避范式（PEAP），以量化疼痛刺激引起的负性情绪水平。通过向 rACC 内注射靶向大鼠 sip30 基因的 shRNA 抑制 CCI 介导的 SIP30 诱导，减少了 PEAP。有趣的是，SIP30 的敲低并不影响 CCI 诱导的诱发痛，如热痛觉过敏和机械性痛觉过敏。它也不影响一般学习和记忆。CCI 诱导的 SIP30 上调与 rACC 中 ERK、PKA 和 CREB 的激活相关。rACC 内给予 PKA 或 ERK 抑制剂可抑制 CCI 诱导的 SIP30 上调，并阻断 PEAP 的诱导。此外，SIP30 的敲低可抑制 rACC 切片中 mEPSC 的频率并增加成对脉冲比，并降低细胞外谷氨酸浓度。总之，我们的结果突出了 SIP30 作为 rACC 中 PKA 和 ERK 的靶点，通过调节谷氨酸释放和兴奋性突触传递来介导神经病理性疼痛引起的负性情绪。
