Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway.
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.
Lam
D K
DK
Department of Oral and Maxillofacial Surgery, University of California - San Francisco, San Francisco, CA, USA.
Schmidt
B L
BL
D000818:Animals; D002277:Carcinoma / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006258:Head and Neck Neoplasms / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D007150:Immunohistochemistry; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D057057:Serine Proteases / Q000187:drug effects / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000503:physiopathology
D017077:Culture Media, Conditioned; D044464:Receptor, PAR-2; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases