Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABAA receptor subtypes

Peng, Hsien-Yu; Chen, Gin-Den; Lee, Shin-Da; Lai, Cheng-Yuan; Chiu, Chun-Hsien; Cheng, Chen-Li; Chang, Yu-Shuo; Hsieh, Ming-Chun; Tung, Kwong-Chung; Lin, Tzer-Bin

doi:10.1016/j.pain.2008.12.023

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Volume 143, Issue 1 , Pages 12-20, May 2009

Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA_A receptor subtypes

Hsien-Yu Peng
- Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan
Gin-Den Chen
- Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan
- These two authors contributed equally to this study.
Shin-Da Lee
- School of Physical Therapy, Graduate Institute of Rehabilitation Science, College of Medicine, China Medical University, Taichung, Taiwan
Cheng-Yuan Lai
- Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan
Chun-Hsien Chiu
- Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan
Chen-Li Cheng
- Urology Division, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
Yu-Shuo Chang
- Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan
Ming-Chun Hsieh
- Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan
Kwong-Chung Tung
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan
Tzer-Bin Lin
- Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan
- Medical Department, Saint Paul’s Hospital, Taoyuan, Taiwan
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
- These two authors contributed equally to this study.
- Corresponding author. Address: Department of Physiology, College of Medicine, Chung-Shan Medical University, No. 110, Chang-Kuo North Rd, Section 1, Taichung 40201, Taiwan. Tel.: +886 4 2473 0022; fax: +886 4 2473 9030.

Received 23 July 2008; received in revised form 15 December 2008; accepted 16 December 2008. published online 02 March 2009.

Abstract

Recently, we demonstrated a spinal GABA_A receptor (GABA_AR)-dependent inhibition on the induction of repetitive stimulation-induced spinal reflex potentiation. However, it remains unclear whether steroid hormones modulate such an inhibition. Here, we show that progesterone is capable of producing GABA_ARs-dependent inhibition of the induction of spinal reflex potentiation by actions through neurosteroid metabolites. Progesterone (5mg/kg, twice daily for 4 days) up-regulates the expression of GABA_AR α2, α3, α4 and δ subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50mg/kg, twice daily), an antagonist of neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30min) intrathecal treatment with the neurosteroids, allopregnanolone (ALLOP, 10μM, 10μL) and 3α,5α-tetrahydrodeoxycorticosterone (THDOC, 10μM, 10μL). Acute intrathecal administration of the GABA_AR antagonist, bicuculline (10μM, 10μL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABA_AR expression and neural inhibition are regulated by neurosteroids synthesis rather than progesterone receptor activation.