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: Alla Khodorova, Betsy Navarro, Laurence Sophie Jouaville, Jo-Ellen Murphy, Frank L Rice, Joseph E Mazurkiewicz, Denise Long-Woodward, Markus Stoffel, Gary R Strichartz, Rus Yukhananov, Gudarz Davar
• Journal: Nature medicine (Nat Med) Vol. 9 Issue 8 Pg. 1055-61 (Aug 2003) ISSN: 1078-8956 [Print] United States
• PMID: 12847519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Endothelin-1
• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• Receptor, Endothelin B
• Receptors, Endothelin
• Receptors, Opioid, delta
• Receptors, Opioid, kappa
• Receptors, Opioid, mu
• beta-Endorphin

Topics

• Analgesia
• Animals
• Cells, Cultured
• Endothelin-1 (metabolism)
• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Humans
• Keratinocytes (cytology, metabolism)
• Male
• Pain (metabolism)
• Pain Measurement
• Potassium Channels (metabolism)
• Potassium Channels, Inwardly Rectifying
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin B
• Receptors, Endothelin (metabolism)
• Receptors, Opioid, delta (metabolism)
• Receptors, Opioid, kappa (metabolism)
• Receptors, Opioid, mu (metabolism)
• Signal Transduction
• Skin (cytology, injuries)
• beta-Endorphin (metabolism)