Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1

Lillian Cruz-Orengo, Ajay Dhaka, Robert J. Heuermann, Timothy J. Young, Michael C. Montana, Eric J. Cavanaugh, Donghee Kim, Gina M. Story

Research output: Contribution to journalArticle

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Abstract

Background: A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of "thermoTRPs," a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues. Results: Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD2 metabolite, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ2 specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ2 and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ2 has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our in vivo studies revealed that 15d-PGJ2 induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors. Conclusion: In conclusion, we show that 15d-PGJ2 induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.

Original languageEnglish (US)
Article number30
JournalMolecular Pain
Volume4
DOIs
StatePublished - Jul 31 2008
Externally publishedYes

Fingerprint

Nociception
Ion Channels
Skin
Spinal Ganglia
Neurons
Prostaglandins
Cysteine
Cinnamomum zeylanicum
Transient Receptor Potential Channels
Cyclopentanes
Prostaglandin D2
Irritants
PPAR gamma
Hyperalgesia
G-Protein-Coupled Receptors
Knockout Mice
9-deoxy-delta-9-prostaglandin D2
15-deoxy-delta(12,14)-prostaglandin J2
Anti-Inflammatory Agents
Lipids

ASJC Scopus subject areas

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine

Cite this

Cruz-Orengo, L., Dhaka, A., Heuermann, R. J., Young, T. J., Montana, M. C., Cavanaugh, E. J., ... Story, G. M. (2008). Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. Molecular Pain, 4, [30]. https://doi.org/10.1186/1744-8069-4-30

Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. / Cruz-Orengo, Lillian; Dhaka, Ajay; Heuermann, Robert J.; Young, Timothy J.; Montana, Michael C.; Cavanaugh, Eric J.; Kim, Donghee; Story, Gina M.

In: Molecular Pain, Vol. 4, 30, 31.07.2008.

Research output: Contribution to journalArticle

Cruz-Orengo, L, Dhaka, A, Heuermann, RJ, Young, TJ, Montana, MC, Cavanaugh, EJ, Kim, D & Story, GM 2008, 'Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1', Molecular Pain, vol. 4, 30. https://doi.org/10.1186/1744-8069-4-30
Cruz-Orengo, Lillian ; Dhaka, Ajay ; Heuermann, Robert J. ; Young, Timothy J. ; Montana, Michael C. ; Cavanaugh, Eric J. ; Kim, Donghee ; Story, Gina M. / Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. In: Molecular Pain. 2008 ; Vol. 4.
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AU - Dhaka, Ajay

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AU - Young, Timothy J.

AU - Montana, Michael C.

AU - Cavanaugh, Eric J.

AU - Kim, Donghee

AU - Story, Gina M.

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