Role of acid-sensing receptor TRPV1 in inflammatory pain

Objectives: Protons have been considered a cause of pain. However, little is known about the precise mechanism by which protons induce inflammatory pain. Recent studies have shown that protons directly activate the transient receptor potential vanilloid subtype1 (TRPV1) that transduces pain signals to the central nervous system. In this study, we investigated the role of TRPV1 in inflammatory pain. Methods: Complete freund's adjuvant (CFA) was injected into the hind paw of wild type (WT) and TRPV1-deficient (TRPV1-/-) mice to induce inflammation. Thermal and mechanical hyperalgesia were evaluated by the plantar test and grip force test, respectively. The expression of calcitonin gene-related peptide (CGRP), a widely-used molecular marker for inflammatory pain, was examined immunohistochemically and the release of CGRP was measured by ELISA. Results: CFA caused swelling and inflammatory cell infiltration in both WT and TRPV1-/- mice to an equivalent extent. WT mice showed thermal hyperalgesia in the CFA-injected hind paw which was reversed by the administration of bafilomycin A1, an inhibitor of the vacuolar H+-ATPase that produces proton. In contrast, TRPV1-/- mice showed significantly reduced hyperalgesia. Consistent with these results, CGRP immunoreactive cells increased 10% in the ipsilateral dorsal root ganglia (DRG) compared with the contralateral DRG in WT mice (p<0.05 Student's t-test). However, no significant changes were detected in TRPV1-/- mice. Moreover, immunohistochemical examination revealed that CGRP and TRPV1 were colocalized in the same cells in the DRG. Treatment of primary DRG neuron cells in culture with pH5.5 increased CGRP expression and release. This stimulatory effect was inhibited by a TRPV1 selective antagonist I-RTX. Conclusion: These results suggest that acid-sensing receptor TRPV1 plays an important role in inflammatory pain by regulating CGRP expression and secretion in DRG neurons.

This work was partly supported by Grant-in-aid (17014058) and 21st Century COE Program of MEXT of Japan