title: Blockade of substance P receptor attenuates osteoporotic pain, but not bone loss, in ovariectomized mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xin-Feng
authors.initials: XF
authors.lastname: Zheng
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Yue-Hui
authors.initials: YH
authors.lastname: Zhang
authors.forename: Yue-Hua
authors.initials: YH
authors.lastname: Yang
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Meng
authors.forename: Sheng-Dan
authors.initials: SD
authors.lastname: Jiang
authors.forename: Lei-Sheng
authors.initials: LS
authors.lastname: Jiang
mesh_terms: D000698:Analgesia; D000700:Analgesics; D000818:Animals; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D064729:Neurokinin-1 Receptor Antagonists / Q000008:administration & dosage*; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology*; D010052:Ovariectomy; D010146:Pain / Q000188:drug therapy*; D011812:Quinuclidines / Q000008:administration & dosage; D018040:Receptors, Neurokinin-1 / Q000502:physiology*
chemical_list: D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; C076851:L 703606