title: GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain.
abstract: Nitric oxide (NO), synthesised by different isoforms of nitric oxide synthase (NOS), has been linked with the development and maintenance of nociception. We studied the role of the inducible isoform, iNOS, in two different rat pain models with an inflammatory component. iNOS was immunohistochemically detected locally in the paw 6h after Freund's Complete Adjuvant (FCA) injection, showing a plateau at 24-72 h and falling slowly in the following weeks. This correlated with the late phase of the hypersensitivity to pain revealed in the behavioural tests. A highly selective iNOS inhibitor GW274150 (1-30 mg/kg orally, 24h after FCA) suppressed the accumulation of nitrite in the inflamed paw indicating substantial iNOS inhibition. At the same time it partially reversed FCA-induced hypersensitivity to pain and edema in a dose-dependent manner. After Chronic Constriction Injury (CCI) surgery to the sciatic nerve, iNOS presence was only detected locally in the region of the nerve (inflammatory cells). GW274150 (3-30 mg/kg orally, 21 days after surgery) also reversed significantly the CCI-associated hypersensitivity to pain. No iNOS was detectable in dorsal root ganglia, spinal cord or brain in either model. This study demonstrates a role for peripherally-expressed iNOS in pain conditions with an inflammatory component and the potential value of iNOS inhibitors in such conditions.
authors.affiliation: Department of Respiratory Pharmacology, RI CEDD GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK Department of Pain, Neurology+GI CEDD, GlaxoSmithKline Research and Development, New Frontiers Science Park, Third Avenue. Harlow, Essex CM19 5AW, UK Department of Drug Metabolism and Pharmacokinetics, DMPK, GlaxoSmithKline Research and Development Park Road, Ware, Hertfordshire SG12 ODP, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.forename: Nick M
authors.initials: NM
authors.lastname: Clayton
authors.forename: Sue D
authors.initials: SD
authors.lastname: Collins
authors.forename: Philip
authors.initials: P
authors.lastname: Colthup
authors.forename: Iain
authors.initials: I
authors.lastname: Chessell
authors.forename: Richard G
authors.initials: RG
authors.lastname: Knowles
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000175:diagnosis* / Q000201:enzymology*; D007249:Inflammation / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000008:administration & dosage; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D013440:Sulfides / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D013440:Sulfides; C409004:GW 274150; D005620:Freund's Adjuvant; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II