Protease‐activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain

Abstract

These findings suggest that PAR2 may be a key mediator for peripheral sensitization of bone cancer pain. Inhibiting PAR2 activation, especially during the early phase, may be a new therapy for preventing/suppressing development of bone cancer pain.

Increased Expression of Protease-Activated Receptor 2 and 4 Within Dorsal Root Ganglia in a Rat Model of Bone Cancer Pain

“…This means that the expression changes of PAR2 emerged almost concurrently with the behavioral alterations which emerged at DAI 14 and beyond. Upregulation of PAR2 expression in the animal model of bone cancer pain was in agreement with previous reports (Bao et al 2013b;Liu et al 2013).…”

“…Interestingly, the neurochemical changes occur after a tumor-derived nerve injury or remodeling resemble that in other noncancerous neuropathic pain states (Obata et al 2003). The proteases and PAR2 and PAR4 were previously shown to mediate thermal and mechanical hyperalgesia (Asfaha et al 2007;Bao et al 2013a, b;Chen et al 2013;Hoogerwerf et al 2001;Liu et al 2013;Vergnolle et al 2001;Wang et al 2013). Under bone cancer condition, serine proteases and inflammatory factors are released from cancer and associated cells, along with tumor-derived nerve injury or remodeling, which may directly activate PAR2 as well as PAR4 on nociceptive afferents in DRG neurons and result in bone cancer pain.…”

“…In addition to a role in normal pain, recent studies have revealed that PAR2 plays a novel role in mediating acute and chronic cancer pain in ectopic hind paw, head, and neck cancer models (Lam et al 2012;Lam and Schmidt 2010), as well as bone cancer pain models (Bao et al 2013b;Liu et al 2013).…”

Tumour progression and cancer-induced pain: A role for protease-activated receptor-2?

“…Furthermore, supernatants from tumour cells, but not controls, caused marked and prolonged mechanical allodynia in wild type mice when administered into the hind paw. This effect was abolished by serine protease inhibitors and was absent in PAR 2 -deficient mice (Lam and Schmidt, 2010;Lam et al, 2012;Liu et al, 2013).…”

“…The first synthetic PAR 2 antagonists to be developed, FSLLRY-NH 2 and LSIGRL-NH 2 , were based on the activating peptide sequences and were shown to abrogate trypsin-mediated PAR 2 signalling but failed to block peptide agonist-mediated signalling (Al-Ani et al, 2002). The peptide antagonist FSLLRY-NH 2 has been shown to supress proliferation of HT29 colon cancer cells (Ma et al, 2013) as well as alleviating mechanical allodynia and thermal hyperalgesia in rat and mouse models of bone cancer (Bao et al, 2014;Liu et al, 2013) and paclitaxel chemotherapy-induced neuropathy in mice (Chen et al, 2011).…”