title: Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception.
abstract: BACKGROUND
  The Transient Receptor Potential (TRP) ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15-Deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti-nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG) neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation.
  
  
  RESULTS
  Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ2-administered after the induction of inflammation-reduced mechanical hypersensitivity in the Complete Freund's Adjuvant (CFA) model for up to 2 h post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity.
  
  
  CONCLUSIONS
  Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics.
authors.affiliation: Department of Anesthesiology, Washington University Pain Center, St. Louis, MO 63110, USA.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Weng
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Batista-Schepman
authors.forename: Marie E
authors.initials: ME
authors.lastname: Barabas
authors.forename: Eli Q
authors.initials: EQ
authors.lastname: Harris
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Dinsmore
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kossyreva
authors.forename: Audra M
authors.initials: AM
authors.lastname: Foshage
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Wang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schwab
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Wang
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Stucky
authors.forename: Gina M
authors.initials: GM
authors.lastname: Story
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009149:Mustard Plant; D059225:Nociception / Q000187:drug effects*; D010938:Plant Oils / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C477819:15-deoxyprostaglandin J2; D010938:Plant Oils; D011453:Prostaglandins; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D015230:Prostaglandin D2; C027793:mustard oil