• Naoyo Motoyama, Katsuya Morita, Seiji Shiraishi, Tomoya Kitayama, Takashi Kanematsu, Yasuhito Uezono, and Toshihiro Dohi.
• From the *Department of Dental Science for Health Promotion, Division of Integrated Health Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; †Cancer Pathophysiology Division, National Cancer Center Research Institute, Tokyo, Japan; ‡Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen University, Hiroshima, Japan; §Department of Cell & Molecular Pharmacology, Division of Basic Life Science, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; ║Pharmaceutical Education Support Center, Mukogawa Women's University, Nishinomiya, Hyogo, Japan; and ¶Department of Pharmacotherapy, Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan.
• Anesth. Analg.. 2014 Oct 1;119(4):988-95.

BackgroundRecent studies have revealed the antinociceptive effects of glycine transporter (GlyT) inhibitors in neuropathic pain models such as sciatic nerve-injured and diabetic animals. Bone cancer can cause the most severe pain according to complex mechanisms in which a neuropathic element is included. Bone cancer modifies the analgesic action of opioids and limits their effectiveness, and thus novel medicament for bone cancer pain is desired.MethodsFor the femur bone cancer model, NCTC 2472 tumor cells were injected into the medullary cavity of the distal femur of C3H/HeN mice. Effects of GlyT2 inhibitors, ORG 25543 and ALX 1393, and GlyT1 inhibitors, ORG 25935, and knockdown of the expression of spinal GlyTs protein by GlyTs siRNA on pain-like behaviors, such as allodynia, withdrawal threshold, guarding behavior, and limb-use abnormality, were examined in the femur bone cancer model mice. Effects of morphine in combination with GlyT inhibitor were examined.ResultsGlyT2 inhibitors, ORG 25543 and ALX 1393, and GlyT1 inhibitor ORG 25935 by IV or oral administration or knockdown of the expression of spinal GlyTs protein improved pain-like behaviors at 11 days after tumor transplantation. The pain-relief activity was potent and long lasting. Morphine at a dose with no analgesic activity combined with ORG 25543 further promoted the ORG 25543-induced pain-relief activity. Injection of ORG 25543 on the second day after tumor implantation caused 3 phases of pain responses; pain-like behaviors were initially accelerated (at 2-4 days) and subsequently almost disappeared (5-7 days) and then reappeared. Intrathecal injection of strychnine 1 day after injection of ORG 25543 transiently antagonized the pain-relief activity of ORG 25543. In control mice, strychnine improved pain-like behaviors 4 days after tumor implantation and aggravated the behaviors between 4 and 5 days. The evidence suggests that the different mechanisms are phase-dependently involved.ConclusionsGlyT inhibitors with or without morphine may be a new strategy for the treatment of bone cancer pain and lead to further investigations of the mechanisms underlying the development of bone cancer pain.

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