Analgesic effect of bisphosphonates in mice

Bisphosphonates are analogues of inorganic pyrophosphate and are inhibitors of bone resorption. Many derivatives have been developed for the treatment of enhanced bone resorption; several reports reveal that treatment with bi sphosphonates is able to reduce the pain associated with different painful diseases. This study tested the antinociceptive action of four bisphosphona tes, clodronate, alendronate, pamidronate and etidronate, in comparison wit h that of morphine and acetylsalicylic acid using two algesimetric tests in mice, tail-flick and writhing tests. In the tail-flick test, after intrave nous (i.v.) injection, a dose-dependent antinociception was present after p amidronate, clodronate and acetylsalicylic acid whereas etidronate and alen dronate produced an analgesic effect only with the highest dose tested. We also studied the central effect of clodronate and pamidronate and, after in tracerebroventricular injection, both bisphosphonates showed a dose-depende nt antinociceptive effect. In the writhing test clodronate and pamidronate showed a statistically significant antinociceptive action after i.v. and in tramuscular administration. To verify if clodronate and pamidronate could m odulate the peripheral opioid receptors we evaluated the gastrointestinal t ransit time in mice, but we did not find any effect on the gastrointestinal motility. These data indicate that clodronate and pamidronate present a ce ntral and peripheral antinociceptive effect: however, the main mechanism ca nnot be determined from the present data. We discuss the possible pharmacol ogical hypothesis to interpret the present results. The findings suggest a pharmacological role of the bisphosphonates in the modulation of antinocice ption even in acute conditions not related to accelerated osteolytic and in flammatory response, with a possible clinical application to control pain. (C) 2001 International Association for the Study of Pain. Published by Else vier Science B.V. All rights reserved.