Analgesic activity of substance P in rats: tolerance and cross-tolerance with enkephalin.

In rats, tolerance to the analgesic effect of intraventricular substance P (SP) develops quickly. In rats made tolerant to [D-Ala2, D-Leu5]enkephalin the analgesic efficacy of SP is reduced significantly. The latter result suggests some overlap in the sites of action of SP and [D-Ala2,D-Leu5] enkephalin. Since SP seems to lack any direct effect on opiate receptors of the brain, the present data suggest that the analgesic effect of SP is mediated by enkephalin release at supraspinal levels which are related to pain control.