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.
Subject(s)
Analgesia , Pain/metabolism , Potassium Channels, Inwardly Rectifying , Receptors, Endothelin/metabolism , Signal Transduction , Skin/injuries , Animals , Cells, Cultured , Endothelin-1/metabolism , G Protein-Coupled Inwardly-Rectifying Potassium Channels , Humans , Keratinocytes/cytology , Keratinocytes/metabolism , Male , Pain Measurement , Potassium Channels/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Endothelin B , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Skin/cytology , beta-Endorphin/metabolismABSTRACT
Noxious peripheral stimuli increase the sensitivity of central nociceptive neurons to subsequent noxious stimuli. This occurs in part through activation of spinal N-methyl-D-aspartate (NMDA) receptors. These receptors are heteromeric complexes of NMDA-R1 and NMDA-R2 A--D subunits. NMDA-R1 is necessary for the formation of functional NMDA receptors whereas the R2 subunits (A-D) modify the properties of the receptor. However, the role of the various receptor subtypes in nociception has not been established. In this study, we used intrathecally administered phosphodiester antisense oligonucleotides (ODEs) to examine the role of the NMDA-R1, NMDA-R2C and NMDA-R2D subunits in the mediation of formalin-induced nociception in the rat. The antisense ODEs against the NMDA-R1 and NMDAR-2C subunits reduced nociceptive behaviors whereas the corresponding sense ODEs had no effect. In contrast, nociception was unaffected by the antisense ODE to NMDAR-2D. Using an RNase protection assay, we also found that each antisense ODE selectively decreased the level of the corresponding mRNA in the lumbar spinal cord but that the sense ODEs had no such effect. Accordingly, these data provide evidence that the R1 and R2C subunits, but not R2D, of the NMDA receptor participate in the development of formalin-induced nociception.