title: The contribution of the endogenous TRPV1 ligands 9-HODE and 13-HODE to nociceptive processing and their role in peripheral inflammatory pain mechanisms.
abstract: OBJECTIVE
  The transient receptor potential vanilloid type 1 (TRPV1) plays a fundamental role in the detection of heat and inflammatory pain responses. Here we investigated the contribution of two potential endogenous ligands [9- and 13- hydroxyoctadecadienoic acid (HODE)] to TRPV1-mediated noxious responses and inflammatory pain responses.
  
  
  METHODS
  9- and 13-HODE, and their precursor, linoleic acid, were measured in dorsal root ganglion (DRG) neurons and in the hindpaws of control and carrageenan-inflamed rats by liquid chromatography/tandem electrospray mass spectrometry. Calcium imaging studies of DRG neurons were employed to determine the role of TRPV1 in mediating linoleic acid, 9-HODE- and 13-HODE-evoked responses, and the contribution of 15-lipoxygenase to the generation of the HODEs. Behavioural studies investigated the contribution of 9- and 13-HODE and 15-lipoxygenase to inflammatory pain behaviour.
  
  
  RESULTS
  9-HODE (35 ± 7 pmol g(-1)) and 13-HODE (32 ± 6 pmol g(-1)) were detected in hindpaw tissue, but were below the limits of detection in DRGs. Following exposure to linoleic acid, 9- and 13-HODE were detected in DRGs and TRPV1 antagonist-sensitive calcium responses evoked, which were blocked by the 15-lipoxygenase inhibitor PD146176 and an anti-13-HODE antibody. Levels of linoleic acid were significantly increased in the carrageenan-inflamed hindpaw (P < 0.05), whereas levels of 9- and 13-HODE were, however, decreased. Intraplantar co-administration of anti-9- and 13-HODE antibodies and treatment with PD146176 significantly (P < 0.01) attenuated carrageenan-induced hyperalgesia.
  
  
  CONCLUSIONS
  This study demonstrates that, although 9- and 13-HODE can activate TRPV1 in DRG cell bodies, the evidence for a role of these lipids as endogenous peripheral TRPV1 ligands in a model of inflammatory pain is at best equivocal.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alsalem
authors.forename: Amy
authors.initials: A
authors.lastname: Wong
authors.forename: Paul
authors.initials: P
authors.lastname: Millns
authors.forename: Pallavi Huma
authors.initials: PH
authors.lastname: Arya
authors.forename: Michael Siang Liang
authors.initials: MS
authors.lastname: Chan
authors.forename: Andrew
authors.initials: A
authors.lastname: Bennett
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D004195:Disease Models, Animal; D005449:Fluorenes / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D008041:Linoleic Acids / Q000378:metabolism / Q000494:pharmacology*; D044243:Linoleic Acids, Conjugated / Q000378:metabolism*; D008297:Male; D051379:Mice; D010146:Pain / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: C106248:6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene; D005449:Fluorenes; D008041:Linoleic Acids; D044243:Linoleic Acids, Conjugated; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C024347:9-hydroxy-10,12-octadecadienoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D001093:Arachidonate 15-Lipoxygenase