title: An animal model of chronic inflammatory pain: pharmacological and temporal differentiation from acute models.
abstract: Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.
authors.affiliation: Department of Pain Research, Neurology and Gastrointestinal CEDD, GlaxoSmithKline Research and Development Ltd., Harlow, Essex, UK. Alex_W_Wilson@gsk.com
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wilson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Medhurst
authors.forename: Claire I
authors.initials: CI
authors.lastname: Dixon
authors.forename: Nick C
authors.initials: NC
authors.lastname: Bontoft
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Winyard
authors.forename: Kim T
authors.initials: KT
authors.lastname: Brackenborough
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Gunthorpe
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Hicks
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.forename: Daniel S
authors.initials: DS
authors.lastname: McQueen
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
mesh_terms: D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D002908:Chronic Disease; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D005620:Freund's Adjuvant; D007783:Lactones / Q000627:therapeutic use; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D010636:Phenols / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013264:Stifle / Q000502:physiology; D013440:Sulfides / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use; D013997:Time Factors; D016474:Weight-Bearing
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D013440:Sulfides; D013450:Sulfones; C116926:rofecoxib; C409004:GW 274150; D005620:Freund's Adjuvant; D052247:Nitric Oxide Synthase Type II