Therapeutic effects of an NK1 receptor antagonist on mechanical hypersensitivity and bone loss in partial sciatic nerve ligated mice

[Speaker] Daisuke Kodama:1
[Co-author] Yoshiaki Ohi:1, Akira Haji:1
1:Laboratory of Neuropharmacology, School of Pharmacy, Aichi-Gakuin University, Japan

Background: Patients with neuropathic pain frequently express osteoporosis. It has been thought that reduction of mechanical loading causes a lower bone mass in neuropathic pain. Meanwhile, recent studies have revealed that neural systems play an important role in the regulation of bone metabolism. There is a possibility that abnormal neural activity causes a decrease of bone in neuropathic pain patients. In this study, we investigated the impact of neuropathic pain on bone metabolism and effects of analgesics.
Methods: Partial sciatic nerve ligated (PSNL) mice were used as an animal model of neuropathic pain. Pregabalin, a ligand of α2δ subunit of voltage-gated calcium channels, and netupitant, an antagonist of NK1 substance P receptor, were intraperitoneally administrated once daily for 21 days from 7 days after operation. Paw withdrawal threshold was measured by von Frey test, and bone structure was assessed by micro computed tomography.
Results: Mechanical hypersensitivity was developed in the paw of ligated side after 3 days of partial nerve ligation, and it sustained more than 8 weeks. Microarchitecture of distal femur and proximal tibia were evaluated after 2-8 weeks of the operation. In PSNL mice, bone volume, bone volume/tissue volume, trabecular number and thickness significantly decreased, while trabecular separation, trabecular bone pattern factor and structure model index significantly increased in the bones of ligated side. These changes indicate that PSNL mice have osteoporosis in their leg of ligated side. Pregabalin significantly alleviated the reduction of paw withdrawal threshold, but had no effect on bone microarchitecture parameters. On the other hand, netupitant significantly alleviated both mechanical hypersensitivity and bone loss.
Conclusion: Bone loss in PSNL model mice may reflect osteoporosis in neuropathic pain patients, and antagonists of NK1 receptor can be a therapeutic agent for neuropathic pain accompanied with osteoporosis.

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