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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 (ETA) receptors of local nociceptors, it can coincidentally produce analgesia through endothelin-B (ETB) receptors. Here we map a new endogenous analgesic circuit, in which ETB receptor activation induces the release of β-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 ETB receptor–operated opioid pool.

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Figure 1: ETB receptor activation in skin inhibits ET-1-induced pain behavior through μ-opioid receptors and GIRK channels.
Figure 2: Mμ-opioid receptors and GIRK2 channels are expressed on sensory endings in rat plantar hindpaw epidermis.
Figure 3: ETB receptors and β-endorphin colocalize in rat plantar hindpaw epidermis adjacent to nociceptive sensory terminals.
Figure 4: Schematic illustration of the pathway for peripheral endogenous analgesia.

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Acknowledgements

The authors thank D.E. Clapham for discussion on GIRKs and for providing GIRK knockout mice, C. Stein, F. Porreca and J.-G. Gu for help with preparation of the manuscript, and J. Bell for graphical assistance. Supported by the United States Public Health Service (National Cancer Institute), B. Navarro was supported by Kaplan fellowship.

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Correspondence to Gudarz Davar.

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Khodorova, A., Navarro, B., Jouaville, L. et al. Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9, 1055–1061 (2003). https://doi.org/10.1038/nm885

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