Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve.
Many reports have shown the efficacy of cannabinoid agonists in chronic pain, whereas no report exists concerning the potential effect of cannabinoid antagonists following prolonged treatment. We tested the effects of repeated administration of the selective cannabinoid receptor type 1 (CB1) antagonist, SR141716 (rimonabant), in rats with chronic constriction injury of the sciatic nerve (CCI), an animal model of neuropathic pain. The repeated oral administration of SR141716 (1, 3 and 10 mg/kg, once a day for 1 week, from day 7 after the injury) dose dependently attenuated both thermal and mechanical hyperalgesia. A similar effect was observed in CCI wild-type mice, whereas SR141716 was unable to elicit pain relief in CB1 knockout mice, suggesting CB1 receptors involvement in the SR141716-induced antihyperalgesia. The antihyperalgesic activity of SR141716 was associated with a significant reduction of several pro-inflammatory and pro-nociceptive mediators such as tumor necrosis factor alpha (TNFalpha), prostaglandin-E2 (PGE2), lipoperoxide and nitric oxide (NO) levels. The histological analysis of sciatic nerve sections showed a marked degeneration of myelinated fibers in CCI rats, which was substantially reduced after repeated administration of SR141716. This suggests that the compound may favour myelin repair and consequently promote long-lasting functional recovery. This was confirmed by the maintenance of recovery for at least four weeks after treatment discontinuation. In conclusion, the present findings suggest that SR141716 is effective not only in alleviating neuropathic pain but also in favouring the nerve myelin repair.
Costa
Barbara
B
Department of Biotechnology and Bioscience, University of Milano-Bicocca, piazza della Scienza 2, 20126 Milano, Italy. barbara.costa@unimib.it
Trovato
Anna Elisa
AE
Colleoni
Mariapia
M
Giagnoni
Gabriella
G
Zarini
Elena
E
Croci
Tiziano
T
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D063387:Cannabinoid Receptor Antagonists; D003250:Constriction; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000209:etiology; D015232:Dinoprostone / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000172:deficiency; D000077285:Rimonabant; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D020426:Sciatic Neuropathy / Q000150:complications*; D013194:Staining and Labeling / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D063387:Cannabinoid Receptor Antagonists; D008054:Lipid Peroxides; D009419:Nerve Tissue Proteins; D009566:Nitrates; D009573:Nitrites; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D015232:Dinoprostone; D000077285:Rimonabant