Anti-inflammatory and anti-nociceptive activity of risedronate in experimental pain models in rats and mice.
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.
Carvalho
Aline P
AP
Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Ceará, Brazil.
Bezerra
Mirna M
MM
Girão
Virgínia C C
VC
Cunha
Fernando Q
FQ
Rocha
Francisco A C
FA
D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004164:Diphosphonates / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D000068296:Risedronic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004164:Diphosphonates; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D015054:Zymosan; D000068296:Risedronic Acid; D012968:Etidronic Acid; D019342:Acetic Acid