Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain

Yi Dai; Tomoko Moriyama; Tomohiro Higashi; Kazuya Togashi; Kimiko Kobayashi; Hiroki Yamanaka; Makoto Tominaga; Koichi Noguchi

doi:10.1523/JNEUROSCI.0454-04.2004

Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain

J Neurosci. 2004 May 5;24(18):4293-9. doi: 10.1523/JNEUROSCI.0454-04.2004.

Authors

Yi Dai¹, Tomoko Moriyama, Tomohiro Higashi, Kazuya Togashi, Kimiko Kobayashi, Hiroki Yamanaka, Makoto Tominaga, Koichi Noguchi

Affiliation

¹ Department of Anatomy and Neuroscience, Hyogo College of Medicine, Hyogo 663-8501, Japan.

Abstract

Proteinase-activated receptor (PAR) 2 is expressed on a subset of primary afferent neurons and involved in inflammatory nociception. Transient receptor potential vanilloid subfamily 1 (TRPV1) is a sensory neuron-specific cation channel that responds to capsaicin, protons, or heat stimulus. Here, we show that TRPV1 is coexpressed with PAR2 but not with PAR1 or PAR3, and that TRPV1 can functionally interact with PAR2. In human embryonic kidney 293 cells expressing TRPV1 and PAR2, PAR2 agonists increased capsaicin- or proton-evoked TRPV1 currents through a PKC-dependent pathway. After application of PAR2 agonists, temperature threshold for TRPV1 activation was reduced from 42 degrees C to well below the body temperature. PAR2-mediated Fos expression in spinal cord was decreased in TRPV1-deficient mice. The functional interaction was also observed in mouse DRG neurons and proved at a behavioral level. These represent a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by PAR2 activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Endopeptidases / metabolism*
Enzyme Inhibitors / pharmacology
Ganglia, Spinal / metabolism
Ganglia, Spinal / pathology
Humans
Hyperalgesia / genetics
Hyperalgesia / physiopathology
Inflammation / enzymology
Inflammation / physiopathology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons / drug effects
Neurons / metabolism
Neurons / pathology
Pain / enzymology
Pain / physiopathology*
Patch-Clamp Techniques
Protein Kinase C / antagonists & inhibitors
Protein Kinase C / metabolism
Proto-Oncogene Proteins c-fos / metabolism
Receptor, PAR-1 / genetics
Receptor, PAR-1 / metabolism
Receptor, PAR-2 / agonists
Receptor, PAR-2 / genetics
Receptor, PAR-2 / metabolism*
Receptors, Drug / deficiency
Receptors, Drug / genetics
Receptors, Drug / metabolism*
Receptors, Thrombin / genetics
Receptors, Thrombin / metabolism
Signal Transduction / physiology
Spinal Cord / metabolism
Spinal Cord / pathology
Temperature
Transfection

Substances

Enzyme Inhibitors
Proto-Oncogene Proteins c-fos
Receptor, PAR-1
Receptor, PAR-2
Receptors, Drug
Receptors, Thrombin
protease-activated receptor 3
Protein Kinase C
Endopeptidases