Relief of cancer pain by glycine transporter inhibitors.

Abstract

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.

• Authors: Naoyo Motoyama, Katsuya Morita, Seiji Shiraishi, Tomoya Kitayama, Takashi Kanematsu, Yasuhito Uezono, Toshihiro Dohi
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 119 Issue 4 Pg. 988-995 (Oct 2014) ISSN: 1526-7598 [Electronic] United States
• PMID: 25076101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-benzyloxy-3,5-dimethoxy-N-(1-(dimethylaminocyclopently)methyl)benzamide
• ALX 1393
• Benzamides
• Glycine Plasma Membrane Transport Proteins
• Serine

Topics

• Animals
• Benzamides (administration & dosage)
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Drug Therapy, Combination
• Glycine Plasma Membrane Transport Proteins (antagonists & inhibitors, physiology)
• Male
• Mice
• Mice, Inbred C3H
• Pain Management (methods)
• Pain Measurement (drug effects, methods)
• Serine (administration & dosage, analogs & derivatives)