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

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Abstract
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 (3.2m). In separate experiments, impulse activity of single, physiologically characterized sensory C-, Aδ-, and Aβ-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 Aδ-fibers (of 12 Aδ-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 Aβ-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 Aδ-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 ETAreceptors.