title: Pharmacological modulation of brain activity in a preclinical model of osteoarthritis.
abstract: The earliest stages of osteoarthritis are characterized by peripheral pathology; however, during disease progression chronic pain emerges-a major symptom of osteoarthritis linked to neuroplasticity. Recent clinical imaging studies involving chronic pain patients, including osteoarthritis patients, have demonstrated that functional properties of the brain are altered, and these functional changes are correlated with subjective behavioral pain measures. Currently, preclinical osteoarthritis studies have not assessed if functional properties of supraspinal pain circuitry are altered, and if these functional properties can be modulated by pharmacological therapy either by direct or indirect action on brain systems. In the current study, functional connectivity was first assessed in order to characterize the functional neuroplasticity occurring in the rodent medial meniscus tear (MMT) model of osteoarthritis-a surgical model of osteoarthritis possessing peripheral joint trauma and a hypersensitive pain state. In addition to knee joint trauma at week 3 post-MMT surgery, we observed that supraspinal networks have increased functional connectivity relative to sham animals. Importantly, we observed that early and sustained treatment with a novel, peripherally acting broad-spectrum matrix metalloproteinase (MMP) inhibitor (MMPi) significantly attenuates knee joint trauma (cartilage degradation) as well as supraspinal functional connectivity increases in MMT animals. At week 5 post-MMT surgery, the acute pharmacodynamic effects of celecoxib (selective cyclooxygenase-2 inhibitor) on brain function were evaluated using pharmacological magnetic resonance imaging (phMRI) and functional connectivity analysis. Celecoxib was chosen as a comparator, given its clinical efficacy for alleviating pain in osteoarthritis patients and its peripheral and central pharmacological action. Relative to the vehicle condition, acute celecoxib treatment in MMT animals yielded decreased phMRI infusion responses and decreased functional connectivity, the latter observation being similar to what was detected following chronic MMPi treatment. These findings demonstrate that an assessment of brain function may provide an objective means by which to further evaluate the pathology of an osteoarthritis state as well as measure the pharmacodynamic effects of therapies with peripheral or peripheral and central pharmacological action.
authors.affiliation: Translational Sciences, Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA. jaymin.upadhyay@abbott.com
authors.forename: Jaymin
authors.initials: J
authors.lastname: Upadhyay
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Rajasimhan
authors.initials: R
authors.lastname: Rajagovindan
authors.forename: Michelle
authors.initials: M
authors.lastname: Hart
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Hooker
authors.forename: Steven
authors.initials: S
authors.lastname: Cassar
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Ann
authors.initials: A
authors.lastname: Tovcimak
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wald
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.forename: Anthony
authors.initials: A
authors.lastname: Bannon
authors.forename: Jeroen K
authors.initials: JK
authors.lastname: Medema
authors.forename: John
authors.initials: J
authors.lastname: Beaver
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Kamath
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Mark
authors.initials: M
authors.lastname: Day
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D000068579:Celecoxib; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D010003:Osteoarthritis / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D010146:Pain / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib