Cannabinoid-mediated diversity of antinociceptive efficacy of parecoxib in Wistar and Sprague Dawley rats in the chronic constriction injury model of neuropathic pain.
We studied nociceptive behavior and the effects of analgesics in Wistar (Wist) and Sprague Dawley (SPD) rats and in CB1 receptor-deficient mice with neuropathic pain experimentally. Neuropathic pain was induced by loose ligation of the sciatic nerve (chronic constriction injury, CCI). In CCI rats from both strains, cold allodynia and a reduced thermal pain threshold were detected, whereas no effect was found in the hot plate test. Thermal pain threshold was used to study the antinociceptive effects of morphine, gabapentin, and parecoxib 5 days after surgery. Doses of gabapentin and morphine which had no effect on sham-operated animals provoked antinociceptive activity in CCI rats from both strains. An antinociceptive effect of parecoxib was only found in CCI Wist rats. No pharmacokinetic differences were detected between the two strains in parecoxib metabolism. Antinociceptive activity caused by parecoxib was attenuated by the CB1 antagonist rimonabant. To further clarify parecoxib-CB1 interaction, the effect of parecoxib was investigated in CB1-deficient mice and wild-type animals. CCI did not affect thermal pain threshold and mechanical pain threshold was decreased. Parecoxib normalized the altered mechanical pain threshold in CCI wild-type animals, whereas it had only a marginal effect in CB1 receptor deficient mice. Receptor binding experiments showed increased CB1 binding in parecoxib-treated CCI Wist rats. Levels of the CB1 receptor mRNA remained constant in both strains of rats 5 days after surgery. Differences in antinociceptive activity might be due to modification of the cannabinoid system.
Faculty of Medicine, Institute of Pharmacology and Toxicology, O. v. Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany. axel.becker@med.ovgu.de
Axel
A
Becker
Gerd
G
Geisslinger
Radovan
R
Murín
Gisela
G
Grecksch
Volker
V
Höllt
Andreas
A
Zimmer
Helmut
H
Schröder
D000818:Animals; D002186:Cannabinoids / Q000378:metabolism; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D016896:Treatment Outcome
D002186:Cannabinoids; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D043884:Receptor, Cannabinoid, CB1; C409945:parecoxib