Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury.
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.
Khodorova
Alla
A
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.
Navarro
Betsy
B
Jouaville
Laurence Sophie
LS
Murphy
Jo-Ellen
JE
Rice
Frank L
FL
Mazurkiewicz
Joseph E
JE
Long-Woodward
Denise
D
Stoffel
Markus
M
Strichartz
Gary R
GR
Yukhananov
Rus
R
Davar
Gudarz
G
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
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