Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice

LIU An-ran; LIN Zhen-jia; PENG Xiang-ge; LI Ying; ZHENG Yu-fan; TAN Zhi; ZHOU Li-jun; FENG Xia

doi:10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20230523.002

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Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice

Basic Research | 更新时间：2024-02-19

- Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice
- Journal of Sun Yat-sen University(Medical Sciences) Vol. 44, Issue 4, Pages: 607-616(2023)
- 作者机构：
  
  1.中山大学附属第一医院麻醉疼痛科，广东广州 510080
  2.中山大学中山医学院生理教研室//中山大学疼痛研究中心，广东广州 510080
- 作者简介：
  
  FENG Xia； E-mail： fengxia@mail.sysu.edu.cn
- 基金信息：
- DOI：10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20230523.002
  CLC： R758.31
- Published：20 July 2023，
  
  Received：25 March 2023，
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刘安然,林震嘉,彭湘格等.鞘内注射2R， 6R-HNK缓解雌性小鼠的神经病理性疼痛[J].中山大学学报（医学科学版）,2023,44(04):607-616.

LIU An-ran,LIN Zhen-jia,PENG Xiang-ge,et al.Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice[J].Journal of Sun Yat-sen University(Medical Sciences),2023,44(04):607-616.
刘安然,林震嘉,彭湘格等.鞘内注射2R， 6R-HNK缓解雌性小鼠的神经病理性疼痛[J].中山大学学报（医学科学版）,2023,44(04):607-616. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20230523.002.

LIU An-ran,LIN Zhen-jia,PENG Xiang-ge,et al.Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice[J].Journal of Sun Yat-sen University(Medical Sciences),2023,44(04):607-616. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).20230523.002.

摘要

目的

初步探究鞘内注射2R， 6R-羟化去甲氯胺酮（2R， 6R-HNK）对慢性神经病理性疼痛（CNP）的镇痛作用及其机制。

方法

采用坐骨神经选择性损伤（SNI）诱导的CNP模型。将雌性小鼠随机分不同组：假手术或SNI术后3 周或术前30 min/1 d给予溶剂、2R， 6R-HNK、S-ketamine（10 mg/kg腹腔注射或7、21 μmol/L鞘内注射）（每组3 ~ 7只）。采用机械缩足阈值（PWT）和镇痛效率评估2R， 6R-HNK的治疗或预防效果。再用免疫荧光和RT-PCR方法检测背根神经节（DRG）和脊髓背角中蛋白转录及表达水平，并探讨其可能的作用机制。

结果

鞘内注射2R， 6R-HNK剂量依赖地缓解雌性小鼠SNI建模3 周的双侧机械痛敏；其中21 μmol/L 2R， 6R-HNK的镇痛效率达峰时间为2 d，峰值为（75.32±7.69）%。预先鞘内2R， 6R-HNK还能延迟SNI诱导双侧机械痛敏产生2 ~ 3 d。机制上，2R， 6R-HNK预处理不仅显著抑制SNI引起的双侧DRG和脊髓背角浅层神经元异常兴奋，还下调DRG内降钙素基因相关肽（CGRP）及脑源性神经生长因子（BDNF）的高表达。

结论

鞘内注射2R， 6R-HNK通过抑制上行痛觉通路神经元异常兴奋并下调DRG神经元CGRP和BDNF表达从而对CNP产生镇痛作用。

Abstract

Objective

To investigate the analgesic action and mechanism of intrathecal 2R， 6R-hydroxynorketamine （2R， 6R-HNK） on spared nerve injury （SNI）-induced chronic neuropathic pain （CNP） in female mice.

Methods

SNI was used to establish acute and chronic CNP models in female mice. The mice were randomly divided into different groups with administration of vehicle， 2R， 6R-HNK or S-ketamine （10 mg/kg intraperitoneal injection/i.p. or 7， 21 μmol/L intrathecal injection/i.t.） at 3 weeks after or 30 min/1 d before operation （

= 3 - 7 mice/group）. The curative or preventive effect of 2R， 6R-HNK was evaluated by mechanical paw withdrawal threshold （PWT） and the analgesic efficiency. Finally， immunofluorescence and RT-PCR of dorsal root ganglion （DRG） and spinal dorsal horn （SDH） were used to explore the possible mechanisms.

Results

Compared with vehicle， intrathecal injection of 2R， 6R-HNK largely reversed SNI-induced bilateral mechanical allodynia in a delayed-and-dose-dependent way. Among them， 21 μmol/L 2R， 6R-HNK reached its maximum analgesic efficiency （75.32±7.69） % at 2 d. Pre-intrathecal delivery of 2R， 6R-HNK also delayed the development of bilateral mechanical hypersensitivity 2 - 3 d induced by SNI. Mechanically， 2R， 6R-HNK reversed not only the abnormal excitability of neurons in bilateral DRG and superficial SDH， but also the upregulation of calcitonin gene-related peptide （CGRP） and brain-derived nerve growth factor （BDNF） in DRG.

Conclusion

Intrathecal administration of 2R， 6R-HNK exerts an analgesic effect against CNP， probably via suppressing abnormal neuronal excitability in ascending pain pathway as well as down-regulating CGRP and BDNF expression in DRG neurons.

关键词

神经病理性疼痛2R，6R-羟化去甲氯胺酮背根神经节降钙素基因相关肽

Keywords

neuropathic pain2R， 6R-hydroxynorketamine （2R， 6R-HNK）dorsal root ganglioncalcitonin gene-related peptide （CGRP）

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Related Author

LIN Zhen-jia

PENG Xiang-ge

LI Ying

ZHENG Yu-fan

TAN Zhi

ZHOU Li-jun

LI Lin-zhi

CUI Yu

Related Institution

Department of Physiology， Zhongshan School of Medical， Sun Yat-sen University， //Center for Pain Research， Sun Yat-sen University

SunYat-sen University School of Medicine

Department of Anesthesiology， The First Affiliated Hospital， Sun Yat-sen University

Department of Anesthesiology， The First Affiliated Hospital of Sun Yat-sen University

Department of Physiology， Zhongshan School of Medical， Sun Yat-sen University， and Center for Pain Research， Sun Yat-sen University

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