Nociceptin (orphanin FQ), the newly discovered endogenous ligand for the opioid receptor like-1 receptor, profoundly inhibited spontaneous discharges of neurons in the rostral ventrolateral medulla (RVLM) in rat brain slices. This inhibition was concentration-dependent (0.3, 1, 3 and 10 nM) and insensitive to pharmacological blockade of traditional opioid receptors by naloxone. Moreover, nociceptin injected into the RVLM (10 nM, 0.1 μl) in anesthetized rats decreased arterial blood pressure and heart rate by 31% and 15%, respectively. The data obtained in vitro and in vivo suggest that nociceptin has powerful effects on the RVLM neurons involving central control of cardiovascular activity. The negative regulation of cardiovascular activity by nociceptin is not mediated through typical naloxone-sensitive opioid receptors.