Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist.

1. The effect of IL-1ra on response to intraplantar (i.pl.) injection of LPS, carrageenin, bradykinin, TNFalpha, IL-1beta, IL-8, PGE(2) and dopamine was investigated in a model of mechanical hyperalgesia in rats. 2. IL-1ra inhibited hyperalgesic response to LPS, carrageenin, bradykinin, TNFalpha, and IL-1beta, but not responses to IL-8, PGE(2) and dopamine. 3. A sheep anti-rat IL-1ra serum potentiated response to LPS, carrageenin, bradykinin, TNFalpha and IL-1beta but not IL-8. 4. Carrageenin and LPS stimulated and production of immunoreactive TNFalpha, IL-1beta and IL-1ra in the skin of injected paws. 5. The inhibition by IL-1ra of the hyperalgesic response to carrageenin was not affected by antibodies neutralizing IL-4 and IL-10. 6. In mice, IL-1ra inhibited the nociceptive response to i.p. injection of acetic acid. 7. These data suggest that IL-1ra, released at sites of inflammation, limits inflammatory hyperalgesia. This effect is independent of (IL-1ra-induced) IL-4 and IL-10 and appears to be the result of antagonism by IL-1ra of IL-1beta-stimulated eicosanoid production.