1Neuroscience Research Institute, Peking University, Beijing 100191, China
2Institute of Systems Biomedicine, Peking University, Beijing 100191, China
3Department of Pharmacy, Bethune International Peace Hospital Shijiazhuang, Shijiazhuang 050082, China
4Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100007, China
5Institute 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
6Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, School of Basic Medical Sciences, Peking University, Beijing 100191, China
7Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China

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.

Keywords

Neurosteroids; Translocator protein; Spared nerve injury; Thalamus; GABAA receptors

[SpringerLink]