Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury.
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-performance 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 ±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 significantly 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.
Neuroscience Research Institute, Peking University, Beijing, 100191, China.
Meng
M
Zhang
Institute of Systems Biomedicine, Peking University, Beijing, 100191, China.
Jia
J
Liu
Neuroscience Research Institute, Peking University, Beijing, 100191, China.
Meng-Meng
MM
Zhou
Department of Pharmacy, Bethune International Peace Hospital Shijiazhuang, Shijiazhuang, 050082, China.
Honghai
H
Wu
Department of Pharmacy, Bethune International Peace Hospital Shijiazhuang, Shijiazhuang, 050082, China.
Yanning
Y
Hou
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, 100007, China.
Yun-Feng
YF
Li
Institute of Systems Biomedicine, Peking University, Beijing, 100191, China.
Yuxin
Y
Yin
Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, and Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education, Peking University, Beijing, 100191, China.
Lemin
L
Zheng
Neuroscience Research Institute, Peking University, Beijing, 100191, China.
Feng-Yu
FY
Liu
Neuroscience Research Institute, Peking University, Beijing, 100191, China. mingyi@bjmu.edu.cn.
Ming
M
Yi
Neuroscience Research Institute, Peking University, Beijing, 100191, China. ywan@hsc.pku.edu.cn.|Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. ywan@hsc.pku.edu.cn.|Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. ywan@hsc.pku.edu.cn.
You
Y
Wan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018756:GABA Antagonists / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000627:therapeutic use*; D010147:Pain Measurement; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012585:Sciatica / Q000188:drug therapy*; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C100745:Aif1 protein, rat; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018756:GABA Antagonists; D005904:Glial Fibrillary Acidic Protein; D007546:Isoquinolines; D008840:Microfilament Proteins; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D018377:Neurotransmitter Agents; D011687:Purines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D010751:Phosphopyruvate Hydratase; D001640:Bicuculline; C037850:PK 11195
GABAA receptors; Neurosteroids; Spared nerve injury; Thalamus; Translocator protein