Nociceptive reaction and thermal hyperalgesia induced by local ET-1 in mice: a behavioral and Fos study.

The peptide endothelin-1 (ET-1) has been involved in nociception independently of its vasoconstrictor effects. We have studied the direct nociceptive behavior produced by this peptide as well as its ability to induce thermal sensitisation (as measured by the unilateral hot plate method, UHP) when intraplantarly (i.pl.) administered in mice. These behavioural measures were complemented by the quantification of Fos-protein immunoreactivity in the superficial laminae of the dorsal horn spinal neurons located ipsilateral to the injected paw.ET-1 induces licking (60-600 pmol, i.pl.) and thermal hyperalgesia (20-200 pmol, i.pl.) in the injected paw, both effects being inhibited by the coadministration of ET-1 with endothelin type A (ET(A)) receptor antagonist, BQ-123 (0.3-10 nmol), but not with endothelin type B (ET(B)) receptor antagonist, BQ-788 (10 nmol). Moreover, the licking behavior induced by ET-1 was dose-dependently inhibited by the prototypical micro -opioid agonist, morphine. The prior i.pl. administration of ET-1 (200 pmol) to mice subjected to thermal heat stimulus (55+/-1 degrees C, 10 s) increases the number of Fos-immunoreactive dorsal horn spinal neurons compared with the application of noxious heat alone. This effect is inhibited by BQ-123 (10 nmol) but not by BQ-788 (10 nmol).Thus, local ET-1 induces nocifensive behavior and thermal hyperalgesia acting through ET(A) receptors. These same receptors seem to be also involved in the amplification of Fos immunoreactivity induced by ET-1 under heat stimulus in the dorsal horn neurons. These results could help to characterize the role of ET-1 in nociceptive processing, a topic of special interest due to the pathophysiological involvement of this peptide in painful states such as cancer.