Local injection of endothelin-1 produces pain-like behavior and excitationof nociceptors in rats

Neurobehavioral and neurophysiological actions of the peptide endothelin-1 (ET-1) were investigated after subcutaneous plantar hindpaw injections in a dult male Sprague Dawley rats. Hindpaw flinching developed within minutes a fter ET-1 (8-16 nmol) injection, peaked at 30 min, lasted for 60 min, and w as strongly inhibited by the endothelin-A (ETA) receptor antagonist, BQ-123 (3.2 M). In separate experiments, impulse activity of single, physiologica lly characterized sensory C-, A delta-, and A beta -fibers was recorded fro m the sciatic nerve in anesthetized rats after subcutaneous injections of e ndothelin-l (1-20 nmol), alone or together with BQ-123 (3.2 M), into the pl antar 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-depende nt manner. For doses of 16-20 nmol, the mean latency for afferent activatio n after injection of ET-1 was 3.16 +/-0.31 min, and the mean and maximum re sponse frequency were 2.02 +/-0.48 impulses (imp)/sec and 14.0 +/-3.2i mp/s ec, respectively. All 10 nociceptive A delta -fibers (of 12 A delta -fibers studied) also responded to 1-20 nmol of ET-1 in a dose-dependent manner wi th a mean latency of 3.5 +/-0.12 min and mean response frequency of 3.3 +/- 2.3 imp/sec. In contrast, most A beta -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 A delta -fibers tested. These data demonstrate that subcutaneous administration of ET-1 to the rat plantar hindpaw produces pain-like behav ior and selective excitation of nociceptive fibers through activation of ET A receptors.