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The Journal of Neuroscience, July 15, 2001, 21(14):5358-5366

Local Injection of Endothelin-1 Produces Pain-Like Behavior and Excitation of Nociceptors in Rats

Alexander P. Gokin1, 2, Moin U. Fareed1, 3, Hui-Lin Pan4, Guy Hans1, 3, Gary R. Strichartz2, 3, and Gudarz Davar1

1 Molecular Neurobiology of Pain, and 2 Sensory Neurophysiology Laboratories of the Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, and 4 Department of Anesthesiology, Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Neurobehavioral and neurophysiological actions of the peptide endothelin-1 (ET-1) were investigated after subcutaneous plantar hindpaw injections in adult male Sprague Dawley rats. Hindpaw flinching developed within minutes after ET-1 (8-16 nmol) injection, peaked at 30 min, lasted for 60 min, and was strongly inhibited by the endothelin-A (ETA) receptor antagonist, BQ-123 (3.2 M). In separate experiments, impulse activity of single, physiologically characterized sensory C-, Adelta -, and Abeta -fibers was recorded from the sciatic nerve in anesthetized rats after subcutaneous injections of endothelin-1 (1-20 nmol), alone or together with BQ-123 (3.2 M), into the plantar hindpaw receptive fields of these units. All nociceptive C-fibers (31 of 33 C-fibers studied) were excited by ET-1 (1-20 nmol) in a dose-dependent manner. For doses of 16-20 nmol, the mean latency for afferent activation after injection of ET-1 was 3.16 ± 0.31 min, and the mean and maximum response frequency were 2.02 ± 0.48 impulses (imp)/sec and 14.0 ± 3.2 imp/sec, respectively. All 10 nociceptive Adelta -fibers (of 12 Adelta -fibers studied) also responded to 1-20 nmol of ET-1 in a dose-dependent manner with a mean latency of 3.5 ± 0.12 min and mean response frequency of 3.3 ± 2.3 imp/sec. In contrast, most Abeta -fibers (9 of 12) did not respond to ET-1. BQ-123, when coinjected with ET-1, blocked ET-1-induced activation in all C- and Adelta -fibers tested. These data demonstrate that subcutaneous administration of ET-1 to the rat plantar hindpaw produces pain-like behavior and selective excitation of nociceptive fibers through activation of ETA receptors.

Key words: excitability; peripheral nerve; algogenic; C-fiber; nociceptor; cancer

Copyright © 2001 Society for Neuroscience  0270-6474/01/21145358-09$05.00/0


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