Related Experiment Video
Updated: Apr 26, 2026
The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
Relief of cancer pain by glycine transporter inhibitors
Naoyo Motoyama1, Katsuya Morita, Seiji Shiraishi
1From 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.
Background:
Recent 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.
Methods:
For 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.
Results:
GlyT2 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.
Conclusions:
GlyT 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.
Insights
Glycine transporter (GlyT) inhibitors show promise in treating bone cancer pain by reducing pain behaviors. Combining GlyT inhibitors with morphine may offer a novel therapeutic strategy for this severe condition.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Neuropathic pain is a component of bone cancer pain, which is severe and complex.
- Opioid effectiveness is limited in bone cancer pain, necessitating novel treatments.
- Glycine transporter (GlyT) inhibitors have demonstrated antinociceptive effects in other neuropathic pain models.
Purpose of the Study:
- To investigate the efficacy of Glycine transporter (GlyT) inhibitors in a mouse model of bone cancer pain.
- To explore the potential of GlyT inhibitors, alone and in combination with morphine, for treating bone cancer pain.
Main Methods:
- A femur bone cancer model was established by injecting NCTC 2472 tumor cells into the femur of C3H/HeN mice.
- The effects of GlyT2 inhibitors (ORG 25543, ALX 1393) and a GlyT1 inhibitor (ORG 25935) on pain behaviors were assessed.
- Spinal GlyT protein expression was reduced using siRNA, and the effects of GlyT inhibitors in combination with morphine were examined.
Main Results:
- GlyT2 and GlyT1 inhibitors, administered orally or intravenously, significantly improved pain-like behaviors in bone cancer model mice.
- The pain relief was potent and long-lasting, with GlyT inhibitors enhancing morphine's analgesic activity.
- The study observed distinct phases of pain response and identified phase-dependent mechanisms involved in pain modulation.
Conclusions:
- Glycine transporter (GlyT) inhibitors represent a potential new strategy for managing bone cancer pain.
- The combination of GlyT inhibitors with morphine may offer enhanced pain relief.
- Further research is warranted to elucidate the underlying mechanisms of bone cancer pain development and treatment.
Related Concept Videos
01:21Chemotherapy-Induced Nausea and Vomiting: Cannabinoids
Two synthetic agonists of THC,...
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
01:27Chemotherapy-Induced Nausea and Vomiting: 5-HT3 Receptor Antagonists
01:29Chemotherapy-Induced Nausea and Vomiting: Dopamine Receptor Antagonists
Phenothiazines, such as prochlorperazine...
01:25Analgesia and Pain Management
01:23Drugs Affecting GI Tract Motility: Serotonin Receptor Agonists