This Week in The Journal

Abstract

Noxious heat, capsaicin, and molecules released from injured cells activate TRPV1 channels on nociceptor neurons. Calcium influx through the channels triggers the release of inflammatory mediators that feed back onto the same neurons, activating intracellular signaling pathways. These signaling pathways include kinases that phosphorylatevariousresiduesonTRPV1,increasing the responsiveness of the channel to subsequent stimulation. Thus, TRPV1 phosphorylation is a major contributor to heightened pain sensitivity (hyperalgesia) after tissue injury. Limiting TRPV1 phosphorylation might therefore reduce hyperalgesia while leaving protective pain responses intact. This therapeutic potential motivated Chung and colleagues to investigate how phosphorylation of specific residues affects TRPV1-mediated responses under baseline and inflammatory conditions. Protein kinase C (PKC) phosphorylates mouse TRPV1 on serine 801 (S801), and previous work in cultured dorsal root ganglion (DRG) neurons showedthatchangingS801toalanine(S801A) to preclude phosphorylation reduced the ability of the PKC agonist phorbol myristate acetate (PMA) to potentiate responses to capsaicin, heat, and acid. Joseph et al. replicated these effects in DRG neurons from S801A knock-in mice and went on to examine how the mutation affected behavioral responses in vivo. Asexpectedfrom invitrostudies,wild-type and knock-in mice showed similar baseline behavioral sensitivity to noxious thermal and mechanical stimuli.But injectionofPMAinto the paw failed to produce nocifensive responses in knock-in mice as it did in wild-type mice. In addition, the PMA-induced potentiationofnocifensiveresponses tocapsaicinwas diminished in knock-in mice. Furthermore, grimacing responses resulting from inflammation of the masseter muscle were lower in knock-in mice than in controls. Surprisingly, however, the S801A mutation did not reduce thermal hyperalgesia produced by PMA. Moreover, the amount of mechanical and thermalhyperalgesia inducedbymild thermal injuryorinjectionofinflammatoryagentsinto the paw were indistinguishable in wild-type and knock-in mice. These results suggest that PKC-mediated phosphorylation of TRPV1 at S801 increases behavioral sensitivity to capsaicin and to inflammation of the masseter muscle, but does not contribute to thermal or mechanical hypersensitivity inthepaw.This isreminiscentof previous studies showing modality-specific effects of phosphorylation of other TRPV1 residues, and it supports the hypothesis that targeting specific phosphorylation sites on TRPV1 may selectively reverse specific forms of hyperalgesia. See Chung et al. for details.