title: Concurrent validity of different functional and neuroproteomic pain assessment methods in the rat osteoarthritis monosodium iodoacetate (MIA) model.
abstract: Lack of validity in osteoarthritis pain models and assessment methods is suspected. Our goal was to 1) assess the repeatability and reproducibility of measurement and the influence of environment, and acclimatization, to different pain assessment outcomes in normal rats, and 2) test the concurrent validity of the most reliable methods in relation to the expression of different spinal neuropeptides in a chemical model of osteoarthritic pain.
  
  
  
  Repeatability and inter-rater reliability of reflexive nociceptive mechanical thresholds, spontaneous static weight-bearing, treadmill, rotarod, and operant place escape/avoidance paradigm (PEAP) were assessed by the intraclass correlation coefficient (ICC). The most reliable acclimatization protocol was determined by comparing coefficients of variation. In a pilot comparative study, the sensitivity and responsiveness to treatment of the most reliable methods were tested in the monosodium iodoacetate (MIA) model over 21 days. Two MIA (2 mg) groups (including one lidocaine treatment group) and one sham group (0.9 % saline) received an intra-articular (50 μL) injection.
  
  
  
  No effect of environment (observer, inverted circadian cycle, or exercise) was observed; all tested methods except mechanical sensitivity (ICC <0.3), offered good repeatability (ICC ≥0.7). The most reliable acclimatization protocol included five assessments over two weeks. MIA-related osteoarthritic change in pain was demonstrated with static weight-bearing, punctate tactile allodynia evaluation, treadmill exercise and operant PEAP, the latter being the most responsive to analgesic intra-articular lidocaine. Substance P and calcitonin gene-related peptide were higher in MIA groups compared to naive (adjusted P (adj-P) = 0.016) or sham-treated (adj-P = 0.029) rats. Repeated post-MIA lidocaine injection resulted in 34 times lower downregulation for spinal substance P compared to MIA alone (adj-P = 0.029), with a concomitant increase of 17 % in time spent on the PEAP dark side (indicative of increased comfort).
  
  
  
  This study of normal rats and rats with pain established the most reliable and sensitive pain assessment methods and an optimized acclimatization protocol. Operant PEAP testing was more responsive to lidocaine analgesia than other tests used, while neuropeptide spinal concentration is an objective quantification method attractive to support and validate different centralized pain functional assessment methods.
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.|Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Colombe
authors.initials: C
authors.lastname: Otis
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Gervais
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.|Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Guillot
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.
authors.forename: Julie-Anne
authors.initials: JA
authors.lastname: Gervais
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.|Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauvin
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.|Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Péthel
authors.affiliation: CiToxLAB North America Inc., Laval, Quebec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Authier
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Dansereau
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Martel-Pelletier
authors.affiliation: Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelletier
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada.|Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Beaudry
authors.affiliation: Groupe de Recherche en Pharmacologie Animale du Québec (GREPAQ), Department of Biomedical Sciences, Faculty of veterinary medicine, Université de Montréal, 1500 des Vétérinaires Street, P.O. Box 5000, St-Hyacinthe, Quebec, J2S 7C6, Canada. eric.troncy@umontreal.ca.|Osteoarthritis Research Unit, Research Center Hospital of Montreal University (CRCHUM), Montreal, Quebec, Canada. eric.troncy@umontreal.ca.
authors.forename: Eric
authors.identifier: 0000-0003-0209-5261
authors.initials: E
authors.lastname: Troncy
mesh_terms: D000064:Acclimatization / Q000502:physiology; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003216:Conditioning, Operant; D005260:Female; D019807:Iodoacetic Acid / Q000633:toxicity; D009479:Neuropeptides / Q000032:analysis*; D010003:Osteoarthritis / Q000150:complications / Q000378:metabolism; D010146:Pain / Q000209:etiology; D010147:Pain Measurement / Q000379:methods*; D017288:Pain Threshold; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry
chemical_list: D009479:Neuropeptides; D019807:Iodoacetic Acid
keywords: Acclimatization; Animal preclinical model; Methods; Monosodium iodoacetate; Neuropeptide; Osteoarthritis; Pain metrology; Validation