Prostaglandin Metabolite Induces Inhibition of TRPA1 and Channel-Dependent Nociception

Autor: Eli Q Harris, Cheryl L. Stucky, Victoria M Wang, Gina M. Story, Yingqi Weng, Patricia A Batista-Schepman, Marie E. Barabas, Michelle Wang, Audra M Foshage, Matthew J Schwab, Elena A. Kossyreva, Thomas B Dinsmore
Jazyk: angličtina
Předmět:
Male
Nociception
Stimulation
Pharmacology
TRPA1
Mechanical hypersensitivity
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
Transient receptor potential channel
chemistry.chemical_compound
Transient Receptor Potential Channels
15d-PGJ2
0302 clinical medicine
Desensitization (telecommunications)
Dorsal root ganglion
Ganglia
Spinal
lcsh:Pathology
medicine
Animals
Plant Oils
TRPA1 Cation Channel
Negative modulation
Ion channel
030304 developmental biology
Mice
Knockout
0303 health sciences
Prostaglandin D2
Research
food and beverages
Cell biology
medicine.anatomical_structure
Anesthesiology and Pain Medicine
chemistry
Prostaglandins
Molecular Medicine
lipids (amino acids
peptides
and proteins)
Mustard oil
030217 neurology & neurosurgery
psychological phenomena and processes
Mustard Plant
lcsh:RB1-214
Zdroj: Molecular Pain, Vol 8, Iss 1, p 75 (2012)
Molecular Pain
ISSN: 1744-8069
DOI: 10.1186/1744-8069-8-75
Popis: 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.
Databáze: OpenAIRE
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