Endothelin Receptors and Pain

The endogenous endothelin (ET) peptides participate in a remarkable variety of pain-relatedprocesses. Pain that is elevated by inflammation, by skin incision, by cancer, during a Sickle Cell Disease crisis and by treatments that mimic neuropathic and inflammatory pain and are all reduced by local administration of antagonists of endothelin receptors. Many effects of endogenously released endothelin are simulated by acute, local subcutaneous administration of endothelin, which at very high concentrations causes pain and at lower concentrations sensitizes the nocifensive reactions to mechanical, thermal and chemical stimuli. Perspective: In this paper we review the biochemistry, second messenger pathways and hetero-receptor coupling that are activated by ET receptors, the cellular physiological responses to ET receptor activation, and the contribution to pain of such mechanisms occurring in the periphery and the CNS. Our goal is to frame the subject of endothelin and pain for a broad readership, and to present the generally accepted as well as the disputed concepts, including important unanswered questions. (C) 2009 by the American Pain Society