title: Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.
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.
authors.affiliation: Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen University, Hiroshima, Japan; Cancer Pathophysiology, Division National Cancer Center Research Institute, Tokyo, Japan; Department of Cell and Molecular Pharmacology, Division of Basic Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.affiliation: Cancer Pathophysiology, Division National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shiraishi
authors.affiliation: Cancer Pathophysiology, Division National Cancer Center Research Institute, Tokyo, Japan; Department of Dental Science for Health Promotion, Division of Integrated Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Naoyo
authors.initials: N
authors.lastname: Motoyama
authors.affiliation: Department of Cell and Molecular Pharmacology, Division of Basic Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitayama
authors.affiliation: Department of Cell and Molecular Pharmacology, Division of Basic Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.affiliation: Cancer Pathophysiology, Division National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.affiliation: Department of Pharmacotherapy, Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Dohi
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001859:Bone Neoplasms / Q000150:complications* / Q000401:mortality; D003248:Constipation / Q000139:chemically induced; D004195:Disease Models, Animal; D004357:Drug Synergism; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement; D010166:Palliative Care; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D009020:Morphine