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
bisphosphonates is able to reduce the
pain associated with different painful diseases. This study tested the antinociceptive action of four
bisphosphonates,
clodronate,
alendronate,
pamidronate and
etidronate, in comparison with that of
morphine and
acetylsalicylic acid using two algesimetric tests in mice, tail-flick and writhing tests. In the tail-flick test, after intravenous (i.v.) injection, a dose-dependent antinociception was present after
pamidronate,
clodronate and
acetylsalicylic acid whereas
etidronate and
alendronate produced an
analgesic effect only with the highest dose tested. We also studied the central effect of
clodronate and
pamidronate and, after intracerebroventricular injection, both
bisphosphonates showed a dose-dependent antinociceptive effect. In the writhing test
clodronate and
pamidronate showed a statistically significant antinociceptive action after i.v. and intramuscular administration. To verify if
clodronate and
pamidronate could modulate the peripheral
opioid receptors we evaluated the gastrointestinal transit time in mice, but we did not find any effect on the gastrointestinal motility. These data indicate that
clodronate and
pamidronate present a central and peripheral antinociceptive effect; however, the main mechanism cannot be determined from the present data. We discuss the possible pharmacological hypothesis to interpret the present results. The findings suggest a pharmacological role of the
bisphosphonates in the modulation of antinociception even in acute conditions not related to accelerated osteolytic and inflammatory response, with a possible clinical application to control
pain.