Palliation of bone cancer pain by antagonists of platelet-activating factor receptors

PLoS One. 2014 Mar 17;9(3):e91746. doi: 10.1371/journal.pone.0091746. eCollection 2014.

Abstract

Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage
  • Analgesics / pharmacology*
  • Animals
  • Behavior, Animal
  • Bone Neoplasms / complications*
  • Bone Neoplasms / mortality
  • Constipation / chemically induced
  • Disease Models, Animal
  • Drug Synergism
  • Hyperalgesia / drug therapy
  • Hyperalgesia / etiology
  • Male
  • Mice
  • Morphine / administration & dosage
  • Morphine / adverse effects
  • Morphine / pharmacology
  • Pain / drug therapy*
  • Pain / etiology*
  • Pain Measurement*
  • Palliative Care*
  • Platelet Membrane Glycoproteins / antagonists & inhibitors*
  • Platelet Membrane Glycoproteins / genetics
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Spinal Cord / metabolism
  • Treatment Outcome

Substances

  • Analgesics
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor
  • Morphine

Grants and funding

This work was supported in part by Grants-in Aid for Scientific Research (B) 22390349, (C) 21592421 and (C) 24592798 from the Japanese Society for Promotion of Sciences and by the National Cancer Center Research and Development Fund (23-A-30). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.