title: Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis.
abstract: BACKGROUND
  Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.
  
  
  METHODS
  Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.
  
  
  RESULTS
  Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.
  
  
  CONCLUSIONS
  BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.
authors.affiliation: Orthopaedic Molecular Biology Laboratory, Sainte-Justine Hospital Research Centre, 3175 Côte Sainte-Catherine, Montreal, QC, H3T 1C5, Canada. gabriel.kaufman@umontreal.ca
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Kaufman
authors.forename: Charlotte
authors.initials: C
authors.lastname: Zaouter
authors.forename: Barthélémy
authors.initials: B
authors.lastname: Valteau
authors.forename: Pierre
authors.initials: P
authors.lastname: Sirois
authors.forename: Florina
authors.initials: F
authors.lastname: Moldovan
mesh_terms: D000818:Animals; D016118:Anterior Cruciate Ligament / Q000473:pathology / Q000502:physiology / Q000601:surgery; D018771:Arthralgia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D002908:Chronic Disease; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000473:pathology / Q000502:physiology / Q000601:surgery; D008297:Male; D059225:Nociception / Q000187:drug effects*; D020370:Osteoarthritis, Knee / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D016474:Weight-Bearing / Q000502:physiology
chemical_list: C476306:Ac-Orn-(Oic2, alpha-MePhe5, D-betaNal7, Ile8)desArg9-bradykinin; D065169:Bradykinin B1 Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D001920:Bradykinin