Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury  

作　　者：Meng Zhang Jia Liu Meng-Meng Zhou Honghai Wu Yanning Hou Yun-Feng Li Yuxin Yin Lemin Zheng Feng-Yu Liu Ming Yi You Wan 

机构地区：[1]Neuroscience Research Institute, Peking University,Beiiing 100191, China [2]Institute of Systems Biomedicine, Peking University,Beijing 100191, China [3]Department of Pharmacy, Bethune International PeaceHospital Shijiazhuang, Shijiazhuang 050082, China [4]Department of New Drug Evaluation, Beijing Institute ofPharmacology and Toxicology, Beijing 100007, China [5]Institute of Cardiovascular Sciences and Institute of SystemsBiomedicine, and Key Laboratory of MolecularCardiovascular Sciences of the Ministry of Education, PekingUniversity, Beijing 100191, China [6]Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, School ofBasic Medical Sciences, Peking University, Beijing 100191,China [7]Department of Neurobiology, School of Basic MedicalSciences, Peking University, Beijing 100191, China

出　　处：《Neuroscience Bulletin》2016年第4期311-322,共12页神经科学通报（英文版）

基　　金：supported by grants from the National Basic Research Development Program of China(2013CB531905,2014CB548200,and 2015CB554503);the National Natural Science Foundation of China(81230023,81221002,31200835,81571067,and 21305005);a Key Project of the Ministry of Education of China(109003);the ‘‘111’’ Project of the Ministry of Education of China(B07001)

摘　　要：Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors （GABAARs）, which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-perfor mance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids （pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone） in the chronic stage of neuropathic pain （28 days after spared nerve injury） in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus （AP -3.0 mm, ML 4-3.0 mm, DV 6.0 mm） alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were sig- nificantly attenuated by the GABAAR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors （GABAARs）, which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-perfor mance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids （pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone） in the chronic stage of neuropathic pain （28 days after spared nerve injury） in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus （AP -3.0 mm, ML 4-3.0 mm, DV 6.0 mm） alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were sig- nificantly attenuated by the GABAAR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

关 键 词：NEUROSTEROIDS Translocator protein Sparednerve injury THALAMUS GABAA receptors 

分 类 号：R741[医药卫生—神经病学与精神病学]