title: Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors.
abstract: Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA(3) and HXB(3)). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB(3) at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB(3) evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.
authors.affiliation: Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093-0818, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Gregus
authors.forename: Suzanne
authors.initials: S
authors.lastname: Doolen
authors.forename: Darren S
authors.initials: DS
authors.lastname: Dumlao
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Buczynski
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takasusuki
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Fitzsimmons
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Hua
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Taylor
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000502:physiology*
chemical_list: D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D001092:Arachidonate 12-Lipoxygenase; D015126:8,11,14-Eicosatrienoic Acid