Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury |
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Authors: | 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 |
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Institution: | 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;Neuroscience Research Institute,Peking University;Institute of Systems Biomedicine,Peking University;Department of Pharmacy,Bethune International Peace Hospital Shijiazhuang;Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology;Institute of Cardiovascular Sciences and Institute of Systems Biomedicine,and Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education,Peking University;Key Laboratory for Neuroscience,Ministry of Education/National Health and Family Planning Commission,School of Basic Medical Sciences,Peking University;Department of Neurobiology,School of Basic Medical Sciences,Peking University; |
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Abstract: | 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. |
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