Portal de Periódicos da CAPES

Mechanism of Cancer Pain

2010; Volume: 10; Issue: 3 Linguagem: Inglês

10.1124/mi.10.3.7

1543-2548

Brian L. Schmidt, Darryl T. Hamamoto, D. A. Simone, George L. Wilcox,

Pharmacological Receptor Mechanisms and Effects

Nociceptive Mediators and ModulatorsOur review of cancer microenvironmental factors will be confined to those mediators for which there is direct evidence of nociceptive activity.We will not discuss mediators that have been implicated solely on the basis of drug administration [e.g., a COX-2 inhibitor (4)] or techniques directed outside the cancer microenvironment [e.g., downregulation of Toll-like receptor intrathecally (5)].We also omit from review several nociceptive mediators that are secreted in high levels by certain cancers, including glutamate, cytokines, growth factors, and nitric oxide, because published data do not show that peripheral antagonism of these mediators attenuates cancer-induced nociception.The mediators under review here will be endothelin, protons, proteases, bradykinin, nerve growth factor, and tumor necrosis factor (Figure 1).Endogenous modulators that reverse cancer-induced nociception are also discussed, including cannabinoid receptor agonists. Endothelin-1: A Dual Role in Cancer-Induced NociceptionThe effects of endothelin-1 (ET-1) on cancer pain are unexpectedly complex.The key to understanding these effects is the activity of two endothelin receptor subtypes that differentially affect opioid release from carcinomas.ET-1 is a potent vasoactive peptide that produces nociceptive behavior in animals and humans (6-8) and drives cancer pain (9).Although ET-1 is produced by multiple cancers, it is not produced by all malignancies (10).ET-1 binds to two G protein-coupled receptors, the endothelin-A receptor (ET A R) and the endothelin-B receptor (ET B R). ET A Rs are distributed on peripheral sensory neurons; ET B Rs are