title: Afferent drive elicits ongoing pain in a model of advanced osteoarthritis.
abstract: Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (ie, ongoing pain) that is generally resistant to nonsteroidal antiinflammatory drugs. Injection of monosodium iodoacetate (MIA) into the intraarticular space of the rodent knee is a well-established model of OA that elicits weight-bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intraarticular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA-induced weight asymmetry but failed to block MIA-induced ongoing pain. Systemic AMG9810, a transient receptor potential V1 channel (TRPV1) antagonist, effectively blocked thermal hypersensitivity, but failed to block high-dose MIA-induced weight asymmetry or ongoing pain. Additionally, systemic or intraarticular HC030031, a TRPA1 antagonist, failed to block high-dose MIA-induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intraarticular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Alec
authors.initials: A
authors.lastname: Okun
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Jiyang
authors.initials: J
authors.lastname: Ren
authors.forename: Bethany
authors.initials: B
authors.lastname: Remeniuk
authors.forename: Triza
authors.initials: T
authors.lastname: Brion
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Jennifer
authors.initials: J
authors.lastname: Xie
authors.forename: Gregory O
authors.initials: GO
authors.lastname: Dussor
authors.forename: Tamara
authors.initials: T
authors.lastname: King
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007270:Injections, Intra-Articular; D008012:Lidocaine / Q000008:administration & dosage; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010003:Osteoarthritis / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D010146:Pain / Q000150:complications / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D050916:TRPV Cation Channels / Q000502:physiology; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D008012:Lidocaine