1. The antinociceptive effect of
risedronate in experimental
pain models in rats and mice was investigated in the present study. 2. Rats received
zymosan intra-articularly (i.art.) into the right knee joint and the nociceptive response was assessed using the articular incapacitation test. Joint washouts were used for determining cell influx, tumour
necrosis factor (
TNF)-alpha and
leukotriene (LT) B4 levels. 3. Mice received either
zymosan (1 mg) or
acetic acid (0.6%) i.p. and the nociceptive response was measured as the number of writhings between 0 and 30 min after the stimuli. Control animals received i.p.
injections of saline. 4. Groups were pretreated with
risedronate (5-500 microg/kg, s.c.) and compared with vehicle (saline)-treated (NT) animals. One group of rats was cotreated with the micro-
opioid receptor antagonist naloxone (2 mg/kg, s.c.) prior to
risedronate, followed by 1 mg
zymosan i.art. 5.
Risedronate, at 100 and 500 microg/kg, significantly and dose-dependently inhibited the nociceptive response in the writhings test (P < 0.05), inhibiting responses to
acetic acid by 65.4 and 49.2%, respectively, and to
zymosan by 72.9 and 71.9%, respectively. 6. Pretreatment with
risedronate also significantly (P < 0.05) and dose-dependently inhibited the articular incapacitation in
zymosan-
arthritis. 7.
Risedronate, at 50 microg/kg, significantly inhibited
TNF-alpha release as compared with the NT group (39.4 +/- 9.8 vs 145.6 +/- 43.3 pg/mL
TNF-alpha, respectively). 8.
Risedronate, at 50 and 100 microg/kg, significantly inhibited
LTB4 release into the joints compared with the NT group (2883.1 +/- 73.2, 1911.5 +/- 205.3 and 4709.9 +/- 237.2 pg/mL, respectively). These effects of
risedronate were associated with a significant reduction in the inflammatory cell infiltration. 9. Cotreatment with
risedronate and
naloxone did not reverse the antinociceptive effects of
risedronate in
zymosan-
arthritis. 10. This is the first demonstration that
risedronate displays intrinsic antihypernociceptive activity. This effect is associated with reduced cell infiltration and inhibition of
TNF-alpha and
LTB4 release and is not linked to an endogenous
opioid-release mechanism.