title: Lysophosphatidic acid provides a missing link between osteoarthritis and joint neuropathic pain.
abstract: Emerging evidence suggests that osteoarthritis (OA) has a neuropathic component; however, the identity of the molecules responsible for this peripheral neuropathy is unknown. The aim of this study was to determine the contribution of the bioactive lipid lysophosphatidic acid (LPA) to joint neuropathy and pain.
  
  
  
  Male Lewis rats received an intra-articular injection of 50 μg of LPA into the knee and allowed to recover for up to 21 days. Saphenous nerve myelination was assessed by g-ratio calculation from electron micrographs and afferent nerve damage visualised by activation transcription factor-3 (ATF-3) expression. Nerve conduction velocity was measured electrophysiologically and joint pain was determined by hindlimb incapacitance. The effect of the LPA antagonist Ki-16425 was also evaluated. Experiments were repeated in the sodium monoiodoacetate (MIA) model of OA.
  
  
  
  LPA caused joint nerve demyelination which resulted in a drop in nerve conduction velocity. Sensory neurones were ATF-3 positive and animals exhibited joint pain and knee joint damage. MIA-treated rats also showed signs of demyelination and joint neuropathy with concomitant pain. Nerve damage and pain could be ameliorated by Ki-16425 pre-treatment.
  
  
  
  Intra-articular injection of LPA caused knee joint neuropathy, joint damage and pain. Pharmacological blockade of LPA receptors inhibited joint nerve damage and hindlimb incapacitance. Thus, LPA is a candidate molecule for the development of OA nerve damage and the origin of joint neuropathic pain.
authors.affiliation: Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada; Department of Anaesthesia, Pain Management & Perioperative Medicine, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada. Electronic address: jason.mcdougall@dal.ca.
authors.forename: J J
authors.initials: JJ
authors.lastname: McDougall
authors.affiliation: Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada; Department of Anaesthesia, Pain Management & Perioperative Medicine, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada. Electronic address: sm668229@dal.ca.
authors.forename: S
authors.initials: S
authors.lastname: Albacete
authors.affiliation: Department of Pharmacology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada; Department of Anaesthesia, Pain Management & Perioperative Medicine, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada. Electronic address: niklas.schuelert@gmail.com.
authors.forename: N
authors.initials: N
authors.lastname: Schuelert
authors.affiliation: MedinCell, 1 Avenue Charles Cros, 34830, Jacou, France. Electronic address: peter.mitchell@medincell.eu.
authors.forename: P G
authors.initials: PG
authors.lastname: Mitchell
authors.affiliation: Lilly Research Laboratories, Eli Lilly Pharmaceuticals, Indianapolis, IN, 46285, USA. Electronic address: lin_chaohua@lilly.com.
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.affiliation: Lilly Research Laboratories, Eli Lilly Pharmaceuticals, Indianapolis, IN, 46285, USA. Electronic address: oskins_jennifer_leigh@lilly.com.
authors.forename: J L
authors.initials: JL
authors.lastname: Oskins
authors.affiliation: Lilly Research Laboratories, Eli Lilly Pharmaceuticals, Indianapolis, IN, 46285, USA. Electronic address: bui_hai_hoang@lilly.com.
authors.forename: H H
authors.initials: HH
authors.lastname: Bui
authors.affiliation: Lilly Research Laboratories, Eli Lilly Pharmaceuticals, Indianapolis, IN, 46285, USA. Electronic address: chambers_mark_geoffrey@lilly.com.
authors.forename: M G
authors.initials: MG
authors.lastname: Chambers
mesh_terms: D051700:Activating Transcription Factor 3 / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018771:Arthralgia; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001522:Behavior, Animal; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D006801:Humans; D007270:Injections, Intra-Articular; D019807:Iodoacetic Acid / Q000633:toxicity; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction / Q000187:drug effects*; D009437:Neuralgia; D010003:Osteoarthritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D020370:Osteoarthritis, Knee / Q000378:metabolism; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011422:Propionates / Q000494:pharmacology; D011917:Rats, Inbred Lew; D013582:Synovial Fluid / Q000737:chemistry
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; C032881:lysophosphatidic acid; D019807:Iodoacetic Acid
keywords: Animal models; Arthritis; Electrophysiology; Joint nerves; Lipid mediators; Neuropathic pain