Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception
<p>Abstract</p> <p>Background</p> <p>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, 1...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2012-09-01
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| Series: | Molecular Pain |
| Subjects: | |
| Online Access: | http://www.molecularpain.com/content/8/1/75 |
| _version_ | 1818497101282148352 |
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| author | Weng Yingqi Batista-Schepman Patricia A Barabas Marie E Harris Eli Q Dinsmore Thomas B Kossyreva Elena A Foshage Audra M Wang Michelle H Schwab Matthew J Wang Victoria M Stucky Cheryl L Story Gina M |
| author_facet | Weng Yingqi Batista-Schepman Patricia A Barabas Marie E Harris Eli Q Dinsmore Thomas B Kossyreva Elena A Foshage Audra M Wang Michelle H Schwab Matthew J Wang Victoria M Stucky Cheryl L Story Gina M |
| author_sort | Weng Yingqi |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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 J<sub>2</sub> (15d-PGJ<sub>2</sub>) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ<sub>2</sub> 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-PGJ<sub>2</sub>. To investigate this, we utilized a battery of behavioral assays and intracellular Ca<sup>2+</sup> imaging in DRG neurons to test if pre-treatment with 15d-PGJ<sub>2</sub> inhibited TRPA1 to subsequent stimulation.</p> <p>Results</p> <p>Intraplantar pre-injection of 15d-PGJ<sub>2</sub>, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ<sub>2</sub> and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ<sub>2</sub>—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-PGJ<sub>2</sub>-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca<sup>2+</sup> imaging studies of DRG neurons demonstrated that 15d-PGJ<sub>2</sub> 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-PGJ<sub>2</sub> combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ<sub>2</sub> depend on TRPA1 activation. Single daily doses of 15d-PGJ<sub>2</sub>, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity.</p> <p>Conclusions</p> <p>Taken together, our data support the hypothesis that 15d-PGJ<sub>2</sub> induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons <it>in vitro</it> and <it>in vivo</it>. Moreover, we demonstrate novel evidence that 15d-PGJ<sub>2</sub> 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.</p> |
| first_indexed | 2024-12-10T18:41:10Z |
| format | Article |
| id | doaj.art-b1d055b5cd7145f0a75c36272cd6c4af |
| institution | Directory Open Access Journal |
| issn | 1744-8069 |
| language | English |
| last_indexed | 2024-12-10T18:41:10Z |
| publishDate | 2012-09-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Molecular Pain |
| spelling | doaj.art-b1d055b5cd7145f0a75c36272cd6c4af2022-12-22T01:37:39ZengSAGE PublishingMolecular Pain1744-80692012-09-01817510.1186/1744-8069-8-75Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociceptionWeng YingqiBatista-Schepman Patricia ABarabas Marie EHarris Eli QDinsmore Thomas BKossyreva Elena AFoshage Audra MWang Michelle HSchwab Matthew JWang Victoria MStucky Cheryl LStory Gina M<p>Abstract</p> <p>Background</p> <p>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 J<sub>2</sub> (15d-PGJ<sub>2</sub>) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ<sub>2</sub> 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-PGJ<sub>2</sub>. To investigate this, we utilized a battery of behavioral assays and intracellular Ca<sup>2+</sup> imaging in DRG neurons to test if pre-treatment with 15d-PGJ<sub>2</sub> inhibited TRPA1 to subsequent stimulation.</p> <p>Results</p> <p>Intraplantar pre-injection of 15d-PGJ<sub>2</sub>, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ<sub>2</sub> and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ<sub>2</sub>—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-PGJ<sub>2</sub>-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca<sup>2+</sup> imaging studies of DRG neurons demonstrated that 15d-PGJ<sub>2</sub> 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-PGJ<sub>2</sub> combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ<sub>2</sub> depend on TRPA1 activation. Single daily doses of 15d-PGJ<sub>2</sub>, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity.</p> <p>Conclusions</p> <p>Taken together, our data support the hypothesis that 15d-PGJ<sub>2</sub> induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons <it>in vitro</it> and <it>in vivo</it>. Moreover, we demonstrate novel evidence that 15d-PGJ<sub>2</sub> 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.</p>http://www.molecularpain.com/content/8/1/75TRPA115d-PGJ<sub>2</sub>Mustard oilNegative modulationMechanical hypersensitivity |
| spellingShingle | Weng Yingqi Batista-Schepman Patricia A Barabas Marie E Harris Eli Q Dinsmore Thomas B Kossyreva Elena A Foshage Audra M Wang Michelle H Schwab Matthew J Wang Victoria M Stucky Cheryl L Story Gina M Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception Molecular Pain TRPA1 15d-PGJ<sub>2</sub> Mustard oil Negative modulation Mechanical hypersensitivity |
| title | Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception |
| title_full | Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception |
| title_fullStr | Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception |
| title_full_unstemmed | Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception |
| title_short | Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception |
| title_sort | prostaglandin metabolite induces inhibition of trpa1 and channel dependent nociception |
| topic | TRPA1 15d-PGJ<sub>2</sub> Mustard oil Negative modulation Mechanical hypersensitivity |
| url | http://www.molecularpain.com/content/8/1/75 |
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