TY - JOUR
T1 - Serine proteases and protease-activated receptor 2-dependent allodynia
T2 - A novel cancer pain pathway
AU - Lam, D. K.
AU - Schmidt, B. L.
N1 - Funding Information:
We thank L. Prentice and J. Zhang for technical assistance. This work was supported by a Grant from the NIH/NIDCR R21 DE018561 . The authors declare no conflicts of interest for this study.
PY - 2010/5
Y1 - 2010/5
N2 - Mediators involved in the generation of pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we show that human head and neck carcinoma cells have increased levels of proteolytic activity compared to normal human cell controls. Supernatant from human carcinoma cells, but not controls, caused marked and prolonged mechanical allodynia in mice, when administered into the hindpaw. This nociceptive effect was abolished by serine protease inhibition, diminished by mast cell depletion and absent in PAR2-deficient mice. In addition, non-contact co-culture of trigeminal ganglion neurons with human head and neck carcinoma cells increased the proportion of neurons that exhibited PAR2-immunoreactivity. Our results point to a direct role for serine proteases and their receptor in the pathogenesis of cancer pain. This previously unrecognized cancer pain pathway has important therapeutic implications wherein serine protease inhibitors and PAR2 antagonists may be useful for the treatment of cancer pain.
AB - Mediators involved in the generation of pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we show that human head and neck carcinoma cells have increased levels of proteolytic activity compared to normal human cell controls. Supernatant from human carcinoma cells, but not controls, caused marked and prolonged mechanical allodynia in mice, when administered into the hindpaw. This nociceptive effect was abolished by serine protease inhibition, diminished by mast cell depletion and absent in PAR2-deficient mice. In addition, non-contact co-culture of trigeminal ganglion neurons with human head and neck carcinoma cells increased the proportion of neurons that exhibited PAR2-immunoreactivity. Our results point to a direct role for serine proteases and their receptor in the pathogenesis of cancer pain. This previously unrecognized cancer pain pathway has important therapeutic implications wherein serine protease inhibitors and PAR2 antagonists may be useful for the treatment of cancer pain.
KW - Cancer pain
KW - PAR2
KW - Protease
KW - Protease activated receptor 2
KW - Trypsin
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U2 - 10.1016/j.pain.2010.02.010
DO - 10.1016/j.pain.2010.02.010
M3 - Article
C2 - 20189717
AN - SCOPUS:77951765901
VL - 149
SP - 263
EP - 272
JO - Pain
JF - Pain
SN - 0304-3959
IS - 2
ER -