title: GW406381, a novel COX-2 inhibitor, attenuates spontaneous ectopic discharge in sural nerves of rats following chronic constriction injury.
abstract: There are several lines of evidence to suggest that cyclooxygenase-2 (COX-2) plays an important role in the generation and maintenance of neuropathic pain states following peripheral nerve injury. However, COX-2 inhibitors are generally ineffective in reversing mechanical allodynia and hyperalgesia in models of neuropathic hypersensitivity. Here, we have investigated the effects of GW406381, a novel COX-2 inhibitor, on mechanical allodynia, hyperalgesia and generation of spontaneous ectopic discharge in rats following chronic constriction injury (CCI) of the sciatic nerve and compared it with rofecoxib. GW406381 (5mg/kg, 5 days of treatment) significantly reversed the CCI-induced decrease in paw withdrawal thresholds (PWTs), assessed using both von Frey hair and paw pressure tests, whereas an equi-effective dose of rofecoxib (5mg/kg, 5 days of treatment) in inflammatory pain models was ineffective. In rats treated with GW406381, the proportion of fibres showing spontaneous activity was significantly lower (15.58%) than that in the vehicle (32.67%)- and rofecoxib (39.66%)-treated rats. Ibuprofen, a non-selective COX inhibitor, at 5mg/kg, orally dosed three times a day for 5 days did not significantly affect the PWTs in CCI rats. In naïve rats, GW406381 did not significantly change the PWTs. These results illustrate that COX-2 may indeed play an important role in the maintenance of neuropathic pain following nerve injury, but that only certain COX-2 inhibitors, such as GW406381, are effective in this paradigm. Whilst the mechanisms underlying this differential effect of GW406381 are not clear, differences in drug/enzyme kinetic interactions may be a key contributing factor.
authors.affiliation: NeuroSolutions Ltd, P.O. Box 3517, Coventry CV4 7ZS, UK. fyzhao@neurosolutionsltd.com <fyzhao@neurosolutionsltd.com>
authors.forename: Fei-Yue
authors.initials: FY
authors.lastname: Zhao
authors.forename: Dave
authors.initials: D
authors.lastname: Spanswick
authors.forename: Jo C
authors.initials: JC
authors.lastname: Martindale
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Reeve
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006841:Hydrocarbons, Aromatic / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D007783:Lactones / Q000008:administration & dosage; D008297:Male; D009408:Nerve Compression Syndromes / Q000188:drug therapy / Q000503:physiopathology*; D009584:Nitrogen / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects; D011720:Pyrazoles; D011724:Pyridazines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000008:administration & dosage; D013497:Sural Nerve / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C469818:GW406381X; D006841:Hydrocarbons, Aromatic; D007783:Lactones; D011720:Pyrazoles; D011724:Pyridazines; D013450:Sulfones; C116926:rofecoxib; D009584:Nitrogen