The contribution of the endogenous TRPV1 ligands 9-HODE and 13-HODE to nociceptive processing and their role in peripheral inflammatory pain mechanisms.

Abstract

BACKGROUND AND PURPOSE:

The transient receptor potential vanilloid type 1 (TRPV1) plays a fundamental role in the detection of heat and inflammatory pain responses. Here we investigated the contribution of two potential endogenous ligands [9- and 13- hydroxyoctadecadienoic acid (HODE)] to TRPV1-mediated noxious responses and inflammatory pain responses.

EXPERIMENTAL APPROACH:

9- and 13-HODE, and their precursor, linoleic acid, were measured in dorsal root ganglion (DRG) neurons and in the hindpaws of control and carrageenan-inflamed rats by liquid chromatography/tandem electrospray mass spectrometry. Calcium imaging studies of DRG neurons were employed to determine the role of TRPV1 in mediating linoleic acid, 9-HODE- and 13-HODE-evoked responses, and the contribution of 15-lipoxygenase to the generation of the HODEs. Behavioural studies investigated the contribution of 9- and 13-HODE and 15-lipoxygenase to inflammatory pain behaviour.

KEY RESULTS:

9-HODE (35 ± 7 pmol g(-1)) and 13-HODE (32 ± 6 pmol g(-1)) were detected in hindpaw tissue, but were below the limits of detection in DRGs. Following exposure to linoleic acid, 9- and 13-HODE were detected in DRGs and TRPV1 antagonist-sensitive calcium responses evoked, which were blocked by the 15-lipoxygenase inhibitor PD146176 and an anti-13-HODE antibody. Levels of linoleic acid were significantly increased in the carrageenan-inflamed hindpaw (P < 0.05), whereas levels of 9- and 13-HODE were, however, decreased. Intraplantar co-administration of anti-9- and 13-HODE antibodies and treatment with PD146176 significantly (P < 0.01) attenuated carrageenan-induced hyperalgesia.

CONCLUSIONS AND IMPLICATIONS:

This study demonstrates that, although 9- and 13-HODE can activate TRPV1 in DRG cell bodies, the evidence for a role of these lipids as endogenous peripheral TRPV1 ligands in a model of inflammatory pain is at best equivocal.

• Authors: Mohammad Alsalem, Amy Wong, Paul Millns, Pallavi Huma Arya, Michael Siang Liang Chan, Andrew Bennett, David A Barrett, Victoria Chapman, David A Kendall
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 168 Issue 8 Pg. 1961-74 (Apr 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23278358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• 6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
• Fluorenes
• Linoleic Acids
• Linoleic Acids, Conjugated
• TRPV Cation Channels
• TRPV1 protein, mouse
• 9-hydroxy-10,12-octadecadienoic acid
• 13-hydroxy-9,11-octadecadienoic acid
• Arachidonate 15-Lipoxygenase

Topics

• Animals
• Arachidonate 15-Lipoxygenase (metabolism)
• Disease Models, Animal
• Fluorenes (pharmacology)
• Ganglia, Spinal (metabolism)
• Inflammation (chemically induced, complications, drug therapy, metabolism)
• Linoleic Acids (metabolism, pharmacology)
• Linoleic Acids, Conjugated (metabolism)
• Male
• Mice
• Pain (complications, drug therapy, metabolism)
• Rats, Sprague-Dawley
• TRPV Cation Channels (metabolism)