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Blockade of substance P receptor attenuates osteoporotic pain, but not bone loss, in ovariectomized mice

Zheng, Xin-Feng MD; Li, Bo MD; Zhang, Yue-Hui MD, PhD; Yang, Yue-Hua MD; Meng, Xiang-Yu MD; Jiang, Sheng-Dan MD, PhD; Jiang, Lei-Sheng MD, PhD

doi: 10.1097/GME.0b013e31828837a6
Original Study

Objective The aim of this study was to investigate the effect of a substance P (SP) receptor (NK1 receptor [NK1-R]) antagonist on hyperalgesia and bone metabolism in ovariectomized mice.

Methods Thirty-six 9-week-old mice were subjected to either bilateral ovariectomy or sham surgery. Three weeks after the operation, the mice were treated with either a single-dose injection or 2-week repeated daily administration of L-703606, an NK1-R antagonist. Behavioral tests were performed for pain assessment; tibiae and the third lumbar vertebrae were dissected and assessed for microarchitectural or biomechanical properties. The expressions of SP and NK1-R in the dorsal root ganglia and spinal cord were also evaluated.

Results Both single-dose injection and 2-week repeated injections of L-703606 led to a significant increase in nociceptive threshold in ovariectomized mice. However, the antihyperalgesic effect faded at 2 hours and almost disappeared at 5 hours after a single-dose injection. With the 14-day repeated treatment of ovariectomized mice, the effect was not detectable at 24 hours after the first injection but was obvious at 24 hours after 1-week and 2-week administrations and still existed at 48 hours after the last injection. Ovariectomized mice at the hyperalgesic state had enhanced SP immunoreactivity in the dorsal root ganglia and up-regulated SP and NK1-R expressions in the spinal cord. However, no significant change in serum SP level was detected. Two-week treatment with L-703606 could down-regulate these expressions but failed to salvage the deteriorated trabecular microstructure and reduced compressive strength in ovariectomized mice.

Conclusions Estrogen deficiency–induced hyperalgesia is achieved through up-regulation of SP and NK1-R expressions. Blockade of SP receptor can alleviate pain but cannot ameliorate bone loss. NK1-R antagonist is not recommended for the treatment of estrogen deficiency osteoporosis.

From the 1Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; and 2Department of Spinal Surgery, The Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Province, China.

Received November 2, 2012; revised and accepted January 16, 2013.

Funding/source: This study was supported by the National Natural Science Foundation of China (grants 81000779 and U1032001) and the Commission of Science Technology of Shanghai (grant 11JC1408500).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Lei-Sheng Jiang, MD, PhD, Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, No. 1665, Kong Jiang Road, Shanghai 200092, China. E-mail:

© 2013 by The North American Menopause Society.