Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California 94143, USA.
J Neurosci. 2012 Oct 10;32(41):14178-83. doi: 10.1523/JNEUROSCI.2399-12.2012.
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 that 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 upregulation 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 upregulation 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.
针对癌症患者从急性疼痛向慢性疼痛进展的靶向治疗仍然难以实现。我们在小鼠中开发了三种新的癌症模型，这些模型共同再现了人类急性和慢性头颈部癌症疼痛的解剖学、时间和功能特征。在这些新型癌症模型中，我们使用药理学和遗传学方法，确定蛋白酶激活受体 2 (PAR2) 和丝氨酸蛋白酶之间的相互作用至关重要。我们表明，丝氨酸蛋白酶（如胰蛋白酶）以 PAR2 依赖性方式诱导急性癌症疼痛。慢性癌症疼痛与癌症微环境中丝氨酸蛋白酶的升高以及外周神经中 PAR2 的上调有关。丝氨酸蛋白酶抑制可显著减轻野生型小鼠持续性癌症疼痛的严重程度，但最引人注目的是，PAR2 缺陷型小鼠中慢性癌症疼痛的发展得到了预防。我们的研究结果表明 PAR2 在急性癌症疼痛中起直接作用，并表明 PAR2 的上调可能有利于慢性癌症疼痛的发展和维持。靶向 PAR2-丝氨酸蛋白酶相互作用是治疗急性癌症疼痛和预防慢性癌症疼痛的一种有前途的方法。
