Novel Animal Models of Acute and Chronic Cancer Pain: A Pivotal Role for PAR2

Abstract

Targeted therapy to prevent the progression from acute to chronic pain in cancer patients remains elusive. We developed three novel cancer models in mice that together recapitulate the anatomical, temporal and functional characteristics of acute and chronic head and neck cancer pain in humans. Using pharmacologic and genetic approaches in these novel cancer models, we identified the interaction between protease-activated receptor 2 (PAR2) and serine proteases to be of central importance. We show serine proteases such as trypsin induce acute cancer pain in a PAR2-dependent manner. Chronic cancer pain is associated with elevated serine proteases in the cancer microenvironment and PAR2 up-regulation in peripheral nerves. Serine protease inhibition greatly reduces the severity of persistent cancer pain in wild-type mice but most strikingly, the development of chronic cancer pain is prevented in PAR2-deficient mice. Our results demonstrate a direct role for PAR2 in acute cancer pain and suggest that PAR2 up-regulation may favor the development and maintenance of chronic cancer pain. Targeting the PAR2—serine protease interaction is a promising approach to the treatment of acute cancer pain and prevention of chronic cancer pain.

New insights of nociceptor sensitization in bone cancer pain

“…Recent studies have revealed that in addition to the normal pain, PAR2 also plays a novel role in mediating acute and chronic cancer pain in the ectopic hind paw, head and neck cancer models [105,106] as well as bone cancer pain models [80,107,108]. Our study also demonstrated that subcutaneous administration of the PAR2 antagonist FSLLRY-NH2 almost completely abolished mechanical allodynia and thermal hyperalgesia in a rat model of bone cancer, without any effect on spontaneous pain behavior.…”

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).…”

Increased Expression of Protease-Activated Receptor 2 and 4 Within Dorsal Root Ganglia in a Rat Model of 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).…”