We showed previously that
subcutaneous injection of the injury-associated
peptide mediator
endothelin-1 (ET-1) into the rat plantar hindpaw produces
pain behavior and selective excitation of nociceptors, both through activation of ET(A) receptors likely on nociceptive terminals. The potential role of ET(B) receptor activation in these actions of ET-1-has not been examined. Therefore, in these experiments, we studied the effect of blocking or activating ET(B) receptors on ET-1-induced hindpaw flinching and excitation of nociceptors in rats. An ET(B) receptor-selective antagonist,
BQ-788 (3 mm), coinjected with ET-1 (200 microm) reduced the time-to-peak of flinching and significantly enhanced the average maximal flinch frequency (MFF). In contrast, coinjection of an ET(B) receptor selective agonist,
IRL-1620 (100 or 200 microm), with ET-1 reduced the average MFF and the average total number of flinches. Interestingly, this unexpected inhibitory effect of
IRL-1620 was prevented by the nonselective
opioid receptor antagonist naloxone (2.75 mm). To confirm these inhibitory actions, we studied the effects of
IRL-1620 on ET-1-induced spike responses in single, physiologically characterized nociceptive C-fibers.
IRL-1620 suppressed spike responses to ET-1 in all (n = 12) C-units, with mean and maximum response frequencies of 0.08 +/- 0.02 and 1.5 +/- 0.4 impulses/sec versus 0.32 +/- 0.07 and 4.17 +/- 0.17 impulses/sec for ET-1 alone. In additional support of the behavioral results, coinjection of
naloxone (2.75 mm) completely prevented this inhibitory action of
IRL-1620. These results establish that ET(B) receptor activation inhibits ET-1-induced
pain behavior and nociception in a
naloxone-sensitive manner and point to a previously unrecognized dual modulation of acute nociceptive signaling by ET(A) and ET(B) receptors in cutaneous tissues.