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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Analgesia*
-
Animals
-
Cells, Cultured
-
Endothelin-1 / metabolism
-
G Protein-Coupled Inwardly-Rectifying Potassium Channels
-
Humans
-
Keratinocytes / cytology
-
Keratinocytes / 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
-
Skin / injuries*
-
beta-Endorphin / metabolism
Substances
-
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