title: Anti-inflammatory and anti-nociceptive activity of risedronate in experimental pain models in rats and mice.
abstract: 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.
authors.affiliation: Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Ceará, Brazil.
authors.forename: Aline P
authors.initials: AP
authors.lastname: Carvalho
authors.forename: Mirna M
authors.initials: MM
authors.lastname: Bezerra
authors.forename: Virgínia C C
authors.initials: VC
authors.lastname: Girão
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Francisco A C
authors.initials: FA
authors.lastname: Rocha
mesh_terms: 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
chemical_list: 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