Microinjection of renin-angiotensin system peptides in discrete sites within the rat periaqueductal gray matter elicits antinociception.

The intracerebroventricular administration of renin substrate or angiotensin II evokes antinociception in rodents, but the brain sites where most of the renin-angiotensin system peptides act are not yet known. This study describes the antinociceptive effects of microinjecting porcine renin substrate tetradecapeptide (RS) or angiotensins I (AI), II (AII) or III (AIII) into different regions of the periaqueductal gray matter (PAG), using the rat tail flick test. All the above peptides were effective following administration into several PAG regions. Their antinociceptive effects were strongly evoked from the caudal ventrolateral and ventral PAG, including the dorsal raphe nucleus. A dose-dependent antinociception following administration into the ventrolateral PAG was demonstrated for all peptides studied. The effect of AII from the ventrolateral PAG was inhibited by the previous local administration of saralasin, a non-selective angiotensin receptor antagonist. Moreover, the peak effects of RS and AI occurred later than those of AII and AIII. The time-course of antinociception suggests that longer-chain peptides are locally processed to biologically active smaller-chain peptides. This study shows for the first time the antinociceptive effect of RS, AI, AII and III in well-defined PAG regions, an effect that is receptor mediated for AII.