Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain
Yi Dai, … , Hiroki Yamanaka, Koichi Noguchi
Yi Dai, … , Hiroki Yamanaka, Koichi Noguchi
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1979-1987. https://doi.org/10.1172/JCI30951.
View: Text | PDF | Corrigendum
Research Article Neuroscience Article has an altmetric score of 6

Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

Abstract

Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential A1 (TRPA1) is an excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 and TRPA1 in dorsal root ganglion (DRG) neurons could contribute to the sensation of inflammatory pain. Frequent colocalization of TRPA1 with PAR2 was found in rat DRG neurons. PAR2 activation increased the TRPA1 currents evoked by its agonists in HEK293 cells transfected with TRPA1, as well as DRG neurons. Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP2) suppressed this potentiation. Decrease of plasma membrane PIP2 levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP2. These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.

Authors

Yi Dai, Shenglan Wang, Makoto Tominaga, Satoshi Yamamoto, Tetsuo Fukuoka, Tomohiro Higashi, Kimiko Kobayashi, Koichi Obata, Hiroki Yamanaka, Koichi Noguchi

×

Figure 6

TRPA1 activation-induced nocifensive behaviors that were potentiated by SL-NH2.

Options: View larger image (or click on image) Download as PowerPoint
TRPA1 activation-induced nocifensive behaviors that were potentiated by ...
Animals were pretreated subcutaneously with SL-NH2 or LR-NH2 10 minutes before AITC or cinnamaldehyde injection. (A) Pain response to subcutaneous AITC. AITC (3% in 50 μl liquid paraffin) was injected into the left hind footpad, and the number of paw lifts (left) and duration of paw flinches and licks (right) were measured in the first 2 minutes after injection of AITC. Injection of SL-NH2 or LR-NH2 with vehicle did not cause notable paw lifts or flinches (LR + Veh; SL + Veh). The AITC injections caused significant nocifensive behaviors after SL-NH2 or LR-NH2 pretreatment; however, preinjection of SL-NH2 (10 μg in 50 μl saline) significantly increased the number of paw lifts and the duration of paw flinches and licks, compared with preinjection of LR-NH2 (10 μg in 50 μl saline). ***P < 0.0001, **P < 0.001 versus LR + AITC. (B) The pain response to subcutaneous cinnamaldehyde (Cinna). Cinnamaldehyde (100%, 50 μl) was injected into the left hind footpad, and the number of paw lifts (left) and duration of paw flinches and licks (right) were measured in the first 3-minute period. Note that SL-NH2 preinjection significantly increased the number of paw lifts and the duration of paw flinches and licks compared with LR-NH2 preinjection. *P < 0.05, **P < 0.001 versus LR + Cinna. n = 6 rats in each experiment. ANOVA followed by Fisher’s protected least square difference tests were used in the statistical analysis.