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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 (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.


  1. 1

    McQuay, H. & Moore, A. Introduction. in An Evidence-Based Resource For Pain Relief. (eds. McQuay, H & Moore, A.) 23 (Oxford University Press, Oxford, 1998).

    Google Scholar 

  2. 2

    Scholz, J. & Woolf, C.J. Can we conquer pain? Nat. Neurosci. 5 (suppl. 1), 1062– 1067 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Julius, D. & Basbaum, A.I. Molecular mechanisms of nociception. Nature 413, 203– 210 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Hickey, K.A., Rubanyi, G.M., Paul, R.J. & Highsmith, R.F. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am. J. Physiol. 248, C550– C556 (1985).

    CAS  Article  Google Scholar 

  5. 5

    Yanagisawa, M. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332, 411– 415 (1988).

    CAS  Article  Google Scholar 

  6. 6

    Rubanyi, G.M. & Polokoff, A. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol. Rev. 48, 325– 415 (1994).

    Google Scholar 

  7. 7

    Ahn, G.Y. et al. The expression of endothelin-1 and its binding sites in mouse skin increased after ultraviolet B irradiation or local injection of tumor necrosis factor alpha. J. Dermatol. 25, 78– 84 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Luscher, T.F. & Barton, M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102, 2434– 2440 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Nelson, J. et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat. Med. 1, 944– 949 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Ferreira, S.H., Romitelli, M. & de Nucci, G. Endothelin-1 participation in overt and inflammatory pain. J. Cardiovasc. Pharmacol. 13 (suppl. 5), S220– S222 (1989).

    CAS  Article  Google Scholar 

  11. 11

    Davar, G., Hans, G., Fareed, M.U., Sinnott, C. & Strichartz, G. Behavioral signs of acute pain produced by application of endothelin-1 to rat sciatic nerve. NeuroReport 9, 2279– 2283 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Piovezan, A.P., D'Orleans-Juste, P., Souza, G.E. & Rae, G.A. Endothelin-1-induced ET(A) receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw: modulation by simultaneous ET(B) receptor activation. Br. J. Pharmacol. 129, 961– 968 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Jarvis, M.F. et al. ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain. Eur. J. Pharmacol. 388, 29– 35 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Fareed, M.U., Hans, G., Atanda, A., Strichartz, G. & Davar, G. Pharmacological characterization of acute pain behavior produced by application of endothelin-1 to rat sciatic nerve. J. Pain 1, 46– 53 (2000).

    Article  Google Scholar 

  15. 15

    Gokin, A.P. et al. Local injection of endothelin-1 produces pain-like behavior and excitation of nociceptors in rats. J. Neurosci. 21, 5358– 5366 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Pomonis, J.D., Rogers, S.D., Peters, C.M., Ghilardi, J.R. & Mantyh, P.W. Expression and localization of endothelin receptors: implications for the involvement of peripheral glia in nociception. J. Neurosci. 21, 999– 1006 (2001).

    CAS  Article  Google Scholar 

  17. 17

    De-Melo, J.D., Tonussi, C.R., D'Orleans-Juste, P. & Rae, G.A. Articular nociception induced by endothelin-1, carrageenan and LPS in naive and previously inflamed knee-joints in the rat: inhibition by endothelin receptor antagonists. Pain 77, 261– 269 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Wacnik, P.W. et al. Functional interactions between tumor and peripheral nerve: morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain. J. Neurosci. 21, 9355– 9366 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Carducci, M.A. et al. Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J. Clin. Oncol. 8, 2171– 2180 (2002).

    Article  Google Scholar 

  20. 20

    Khodorova, A., Fareed, M.U., Gokin, A., Strichartz, G.R. & Davar, G. Local injection of a selective endothelin-b receptor agonist inhibits endothelin-1 induced pain-like behavior and excitation of nociceptors in a naloxone-sensitive manner. J. Neurosci. 22, 7788– 7796 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Fields, H.L., Emson, P.C., Leigh, B.K., Gilbert, R.F. & Iversen, L.L. Multiple opiate receptor sites on primary afferent fibers. Nature 284, 351– 353 (1980).

    CAS  Article  Google Scholar 

  22. 22

    Stein, C. Peripheral mechanisms of opioid analgesia. Anesth. Analg. 76, 182– 191 (1993).

    CAS  Article  Google Scholar 

  23. 23

    Machelska, H., Cabot, P.J., Mousa, S.A., Zhang, Q. & Stein, C. Pain control in inflammation governed by selectins. Nat. Med. 4, 1425– 1428 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Akil, H., Mayer, D.J. & Liebeskind, J.C. Comparison in the rat between analgesia induced by stimulation of periacqueducal gray matter and morphine analgesia. C. R. Acad. Sci. Hebd. Seances Acad. Sci. D 274, 3603– 3605 (1972).

    CAS  PubMed  Google Scholar 

  25. 25

    Hughes, J. et al. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258, 577– 580 (1975).

    CAS  Article  Google Scholar 

  26. 26

    Akil, H., Mayer, D.J. & Liebeskind, J.C. Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist. Science 191, 961– 962 (1976).

    CAS  Article  Google Scholar 

  27. 27

    Fields, H.L., Heinricher, M.M. & Mason, P. Neurotransmitters in nociceptive modulatory circuits. Ann. Rev. Neurosci. 14, 219– 245 (1991).

    CAS  Article  Google Scholar 

  28. 28

    Harris, J.A. Descending antinociceptive mechanisms in the brainstem: their role in the animal's defensive system. J. Physiol. (Paris) 90, 15– 25 (1996).

    CAS  Article  Google Scholar 

  29. 29

    Gutstein, H.B., Mansour, A., Watson, S.J., Akil, H. & Fields, H.L. Mu and κ-opioid receptors in periaqueductal gray and rostral ventromedial medulla. NeuroReport 9, 1777– 1781 (1998).

    CAS  Article  Google Scholar 

  30. 30

    Stein, C. The control of pain in peripheral tissue by opioids. N. Engl. J. Med. 332, 168– 590 (1995).

    Article  Google Scholar 

  31. 31

    Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277– 281 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Wettstein, G. & Grouhel, A. Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay. Pharmacol. Biochem. Behav. 53, 411– 416 (1996).

    CAS  Article  Google Scholar 

  33. 33

    Wintzen, M., Yaar, M., Burbach, J.P. & Gilchrest, B.A. Proopiomelanocortin gene product regulation in keratinocytes. J. Invest. Dermatol. 106, 673– 678 (1996).

    CAS  Article  Google Scholar 

  34. 34

    Zanello, S.B, Jackson, D.M. & Holick, M.F. An immunocytochemical approach to the study of beta-endorphin production in human keratinocytes using confocal microscopy. Ann. NY Acad. Sci. 885, 85– 99 (1999).

    CAS  Article  Google Scholar 

  35. 35

    Hargreaves, K.M., Flores, C.M., Dionne, R.A. & Mueller, G.P. The role of pituitary beta-endorphin in mediating corticotropin-releasing factor-induced antinociception. Am. J. Physiol. 258, E235– E242 (1990).

    CAS  PubMed  Google Scholar 

  36. 36

    Mark, M.D. & Herlitze, S. G-protein mediated gating of inward-rectifier K+ channels. Eur. J. Biochem. 267, 5830– 5836 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Rogalski, S.L., Cyr, C. & Chavkin, C. Activation of the endothelin receptor inhibits the G protein-coupled inwardly rectifying potassium channel by a phospholipase A2-mediated mechanism. J. Neurochem. 72, 1409– 1416 (1999).

    CAS  Article  Google Scholar 

  38. 38

    Ikeda, K., Kobayashi, T., Kumanishi, T., Niki, H. & Yano, R. Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia. Neurosci. Res. 38, 113– 116 (2000).

    CAS  Article  Google Scholar 

  39. 39

    Blanchet, C. & Luscher, C. Desensitization of mu-opioid receptor-evoked potassium currents: initiation at the receptor, expression at the effector. Proc. Natl. Acad. Sci. USA 99, 4674– 4679 (2002).

    CAS  Article  Google Scholar 

  40. 40

    Torrecilla, M. et al. G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. J. Neurosci. 22, 432– 834 (2002).

    Article  Google Scholar 

  41. 41

    Mitrovic, I., et al. Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. Proc. Natl. Acad. Sci. USA 100, 271– 276 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Blednov, Y.A., Stoffel, M., Alva, H. & Harris, R.A. A pervasive mechanism for analgesia: Activation of GIRK2 channels. Proc. Natl. Acad. Sci. USA 100, 77– 82 (2003).

    Article  Google Scholar 

  43. 43

    Zhou, Q.L., Strichartz, G. & Davar, G. Endothelin-1 activates ET(A) receptors to increase intracellular calcium in model sensory neurons. NeuroReport 12, 3853– 3857 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Zhou, Z., Davar, G. & Strichartz, G. Endothelin-A receptor dependent enhanced activation gating of tetrodotoxin-resistant sodium currents in rat sensory neurons: a possible mechanism of ET-1 induced pain, J. Neurosci 22, 6325– 6330 (2002).

    CAS  Article  Google Scholar 

  45. 45

    Slominski, A., Wortsman, J., Luger, T., Paus, R. & Solomon, S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol. Rev. 80, 979– 1020 (2000).

    CAS  Article  Google Scholar 

  46. 46

    Peier, A.M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046– 2049 (2002).

    CAS  Article  Google Scholar 

  47. 47

    Zimmermann, M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16, 109– 110 (1983).

    CAS  Article  Google Scholar 

  48. 48

    Signorini, S., Liao, Y.J., Duncan, S.A., Jan, L.Y. & Stoffel, M. Normal cerebellar development but susceptibility to seizures in mice lacking G-protein-coupled, inwardly rectifying K+ channel GIRK2. Proc. Natl. Acad. Sci. USA 94, 923– 927 (1997).

    CAS  Article  Google Scholar 

  49. 49

    Broadbear, J.H. et al. Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, β-funaltrexamine, and β-chlornaltrexamine. J. Pharmacol. Exp. Ther. 294, 933– 940 (2000).

    CAS  PubMed  Google Scholar 

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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).

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