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The Journal of Neuroscience, May 5, 2004, 24(18):4293-4299; doi:10.1523/JNEUROSCI.0454-04.2004

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Cellular/Molecular
Proteinase-Activated Receptor 2-Mediated Potentiation of Transient Receptor Potential Vanilloid Subfamily 1 Activity Reveals a Mechanism for Proteinase-Induced Inflammatory Pain

Yi Dai,¹ Tomoko Moriyama,² Tomohiro Higashi,² Kazuya Togashi,² Kimiko Kobayashi,¹ Hiroki Yamanaka,¹ Makoto Tominaga,² and Koichi Noguchi¹

¹Department of Anatomy and Neuroscience, Hyogo College of Medicine, Hyogo 663-8501, Japan, and ²Department of Cellular and Molecular Physiology, Mie University School of Medicine, Tsu, Mie 514-8507, Japan

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°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.

Key words: proteinase-activated receptor; TRPV1; inflammatory pain; PKC; thermal hyperalgesia; mechanical allodynia

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Received Feb 9, 2004; revised March 18, 2004; accepted March 18, 2004.

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