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 (ET A ) receptor antagonist, BQ-123 (3.2 M). In separate experiments, impulse activity of single, physiologically characterized sensory C-, A␦-, and A-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 dosedependent manner. For doses of 16-20 nmol, the mean latency for afferent activation after injection of ET-1 was 3.16 Ϯ 0.31 min, and the mean and maximum response frequency were 2.02 Ϯ 0.48 impulses (imp)/sec and 14.0 Ϯ 3.2 imp/sec, respectively. All 10 nociceptive A␦-fibers (of 12 A␦-fibers studied) also responded to 1-20 nmol of ET-1 in a dose-dependent manner with a mean latency of 3.5 Ϯ 0.12 min and mean response frequency of 3.3 Ϯ 2.3 imp/sec. In contrast, most A-fibers (9 of 12) did not respond to ET-1. BQ-123, when coinjected with ET-1, blocked ET-1-induced activation in all Cand A␦-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 ET A receptors.
Key words: excitability; peripheral nerve; algogenic; C-fiber; nociceptor; cancerPain is a frequent and disabling consequence of metastatic prostate and breast cancer in humans. The cause of this pain is unknown but may involve mediator-dependent signaling by tumor cells to spinal nerve roots. One candidate mediator, the potent vasoconstrictive peptide and mitogen endothelin-1 (ET-1), is secreted in high concentrations by metastatic prostate and breast cancer cells and is known to induce pain-like behavior in animals and pain in humans (Ferreira et al