title: The Bisphosphonates Clodronate and Etidronate Exert Analgesic Effects by Acting on Glutamate- and/or ATP-Related Pain Transmission Pathways.
abstract: Bisphosphonates (BPs) are typical anti-bone-resorptive drugs, with nitrogen-containing BPs (N-BPs) being stronger than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs have inflammatory/necrotic effects, while the non-N-BPs clodronate and etidronate lack such side effects. Pharmacological studies have suggested that clodronate and etidronate can (i) prevent the side effects of N-BPs in mice via inhibition of the phosphate transporter families SLC20 and/or SLC34, through which N-BPs enter soft-tissue cells, and (ii) also inhibit the phosphate transporter family SLC17. Vesicular transporters for the pain transmitters glutamate and ATP belong to the SLC17 family. Here, we examined the hypothesis that clodronate and etidronate may enter neurons through SLC20/34, then inhibit SLC17-mediated transport of glutamate and/or ATP, resulting in their decrease, and thereby produce analgesic effects. We analyzed in mice the effects of various agents [namely, intrathecally injected clodronate, etidronate, phosphonoformic acid (PFA; an inhibitor of SLC20/34), and agonists of glutamate and ATP receptors] on the nociceptive responses to intraplantar injection of capsaicin. Clodronate and etidronate produced analgesic effects, and these effects were abolished by PFA. The analgesic effects were reduced by N-methyl-D-aspartate (agonist of the NMDA receptor, a glutamate receptor) and α,β-methylene ATP (agonist of the P2X-receptor, an ATP receptor). SLC20A1, SLC20A2, and SLC34A1 were detected within the mouse lumbar spinal cord. Although we need direct evidence, these results support the above hypothesis. Clodronate and etidronate may be representatives of a new type of analgesic drug. Such drugs, with both anti-bone-resorptive and unique analgesic effects without the adverse effects associated with N-BPs, might be useful for osteoporosis.
authors.affiliation: Division of Oral Molecular Regulation, Graduate School of Dentistry, Tohoku University.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shima
authors.forename: Wataru
authors.initials: W
authors.lastname: Nemoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Koichi
authors.initials: K
authors.lastname: Tan-No
authors.forename: Teruko
authors.initials: T
authors.lastname: Takano-Yamamoto
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D019342:Acetic Acid; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D002211:Capsaicin; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use; D012968:Etidronic Acid / Q000494:pharmacology / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D017245:Foscarnet / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008159:Lumbar Vertebrae; D051379:Mice; D008807:Mice, Inbred BALB C; D016202:N-Methylaspartate / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology
chemical_list: D000700:Analgesics; D050071:Bone Density Conservation Agents; D018690:Excitatory Amino Acid Agonists; D050608:Sodium-Phosphate Cotransporter Proteins; D004002:Clodronic Acid; D013373:Substance P; D017245:Foscarnet; D018698:Glutamic Acid; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate; D012968:Etidronic Acid; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D019342:Acetic Acid; D002211:Capsaicin