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Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception.
Mol Pain. 2012 Sep 27; 8:75.MP

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+Show Affiliations

Department of Anesthesiology, Washington University Pain Center, St. Louis, MO 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23013719

Citation

Weng, Yingqi, et al. "Prostaglandin Metabolite Induces Inhibition of TRPA1 and Channel-dependent Nociception." Molecular Pain, vol. 8, 2012, p. 75.
Weng Y, Batista-Schepman PA, Barabas ME, et al. Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception. Mol Pain. 2012;8:75.
Weng, Y., Batista-Schepman, P. A., Barabas, M. E., Harris, E. Q., Dinsmore, T. B., Kossyreva, E. A., Foshage, A. M., Wang, M. H., Schwab, M. J., Wang, V. M., Stucky, C. L., & Story, G. M. (2012). Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception. Molecular Pain, 8, 75. https://doi.org/10.1186/1744-8069-8-75
Weng Y, et al. Prostaglandin Metabolite Induces Inhibition of TRPA1 and Channel-dependent Nociception. Mol Pain. 2012 Sep 27;8:75. PubMed PMID: 23013719.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception. AU - Weng,Yingqi, AU - Batista-Schepman,Patricia A, AU - Barabas,Marie E, AU - Harris,Eli Q, AU - Dinsmore,Thomas B, AU - Kossyreva,Elena A, AU - Foshage,Audra M, AU - Wang,Michelle H, AU - Schwab,Matthew J, AU - Wang,Victoria M, AU - Stucky,Cheryl L, AU - Story,Gina M, Y1 - 2012/09/27/ PY - 2012/02/22/received PY - 2012/09/07/accepted PY - 2012/9/28/entrez PY - 2012/9/28/pubmed PY - 2013/6/8/medline SP - 75 EP - 75 JF - Molecular pain JO - Mol Pain VL - 8 N2 - 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/23013719/Prostaglandin_metabolite_induces_inhibition_of_TRPA1_and_channel_dependent_nociception_ L2 - https://journals.sagepub.com/doi/10.1186/1744-8069-8-75?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -