The Bisphosphonates Clodronate and Etidronate Exert Analgesic Effects by Acting on Glutamate- and/or ATP-Related Pain Transmission Pathways

• Published in: Biological & pharmaceutical bulletin 2016/05/01, Vol.39(5), pp.770-777
• Main Authors: Shima, Kazuhiro, Nemoto, Wataru, Tsuchiya, Masahiro, Tan-No, Koichi, Takano-Yamamoto, Teruko, Sugawara, Shunji, Endo, Yasuo
• Format: Article
• Language: English
• Subjects: Acetic Acid; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - pharmacology; analgesic effect; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; ATP; Bone Density Conservation Agents - pharmacology; Bone Density Conservation Agents - therapeutic use; Capsaicin; clodronate; Clodronic Acid - pharmacology; Clodronic Acid - therapeutic use; etidronate; Etidronic Acid - pharmacology; Etidronic Acid - therapeutic use; Excitatory Amino Acid Agonists - pharmacology; Foscarnet - pharmacology; glutamate; Glutamic Acid - metabolism; Lumbar Vertebrae; Mice; Mice, Inbred BALB C; N-Methylaspartate - pharmacology; Pain - chemically induced; Pain - drug therapy; Pain - metabolism; phosphate transporter; Sodium-Phosphate Cotransporter Proteins - genetics; Spinal Cord - drug effects; Spinal Cord - metabolism; Substance P - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b15-00882

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.