title: Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury.
abstract: Endothelin-1 (ET-1) is a newly described pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A (ET(A)) receptors of local nociceptors, it can coincidentally produce analgesia through endothelin-B (ET(B)) receptors. Here we map a new endogenous analgesic circuit, in which ET(B) receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs, also named Kir-3) linked to opioid receptors on nociceptors. These results indicate the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and establish keratinocytes as an ET(B) receptor-operated opioid pool.
authors.affiliation: Molecular Neurobiology of Pain Laboratory, Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115 USA.
authors.forename: Alla
authors.initials: A
authors.lastname: Khodorova
authors.forename: Betsy
authors.initials: B
authors.lastname: Navarro
authors.forename: Laurence Sophie
authors.initials: LS
authors.lastname: Jouaville
authors.forename: Jo-Ellen
authors.initials: JE
authors.lastname: Murphy
authors.forename: Frank L
authors.initials: FL
authors.lastname: Rice
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Mazurkiewicz
authors.forename: Denise
authors.initials: D
authors.lastname: Long-Woodward
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.forename: Gary R
authors.initials: GR
authors.lastname: Strichartz
authors.forename: Rus
authors.initials: R
authors.lastname: Yukhananov
authors.forename: Gudarz
authors.initials: G
authors.lastname: Davar
mesh_terms: D000698:Analgesia; D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000293:injuries*; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D001615:beta-Endorphin