Nociceptin receptors are densely distributed in the nucleus tractus solitarius pre- and postsynaptically. This study tested whether nociceptin receptors in this brain area are involved in the modulation of baroreceptor reflex. In pentobarbital-anesthetized rats, pharmacological activation of nociceptin receptors with bilateral microinjection of a synthetic peptide agonist, nociceptin, into the nucleus tractus solitarius attenuated baroreflex sensitivity as demonstrated by a marked reduction in baroreflex bradycardia induced by a single dose of intravenous phenylephrine. The inhibitory effect of nociceptin was dose dependent (0.04, 0.2 and 1nmol) and was blocked by pretreatment with microinjection of 1nmol nocistatin, a peptide that can functionally reverse the action of nociceptin. In contrast, injection of an opioid receptor antagonist, naloxone (5nmol), did not modify the inhibition of baroreflex sensitivity induced by nociceptin. Neither nocistatin nor naloxone injected into the nucleus alone had any detectable effect on baseline blood pressure and heart rate and baroreflex bradycardia. These data indicate that the newly discovered nociceptin receptors in the central nervous system possess an inhibitory influence on baroreflex transmission at the level of the nucleus tractus solitarius.