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: Xin-Feng Zheng, Bo Li, Yue-Hui Zhang, Yue-Hua Yang, Xiang-Yu Meng, Sheng-Dan Jiang, Lei-Sheng Jiang
• Journal: Menopause (New York, N.Y.) (Menopause) Vol. 20 Issue 10 Pg. 1074-83 (Oct 2013) ISSN: 1530-0374 [Electronic] United States
• PMID: 23549442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Neurokinin-1 Receptor Antagonists
• Quinuclidines
• Receptors, Neurokinin-1
• L 703606

Topics

• Analgesia
• Analgesics
• Animals
• Female
• Mice
• Mice, Inbred C57BL
• Neurokinin-1 Receptor Antagonists (administration & dosage)
• Osteoporosis (drug therapy, physiopathology)
• Ovariectomy
• Pain (drug therapy)
• Quinuclidines (administration & dosage)
• Receptors, Neurokinin-1 (physiology)