The role(s) of central G-proteins in the regulation of cardiovascular and renal function is unknown. We examined how inhibition/down regulation of central Gi/Go, Gz or Gq proteins altered the characteristic cardiovascular (depressor), renal excretory (diuretic) and plasma AVP (inhibitory) responses to intracerebroventricular (i.c.v.) injection of nociceptin/orphanin FQ (N/OFQ) in rats. Prior to investigation rats were pre-treated i.c.v. with saline vehicle (5 µl, 48-h, N=6), pertussis toxin (PTX; 48-h, 1 µg, N=6), or Gz, Gq, or scrambled oligodeoxynucleotide (ODN) (25 µg, 24-hr, N=6 per group). On the study day, i.c.v. N/OFQ (5.5 nmol) or vehicle (5 µl) was injected into pre-treated conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were recorded and urine collected for 90-min. In vehicle or scrambled ODN groups, i.c.v. N/OFQ decreased MAP and HR and produced water diuresis (sensitive to UFP-101, N/OFQ receptor antagonist). The hypotension and bradycardia, but not diuresis, to N/OFQ were abolished in PTX pre-treated rats. In contrast, i.c.v. ODN pre-treatment markedly blunted (Gz) or augmented (Gq) the diuresis to i.c.v. N/OFQ. In separate studies, the action of central N/OFQ to decrease plasma AVP levels in naive water-restricted rats was differentially altered by i.c.v. Gz ODN (blunted) and Gq ODN (augmented) pre-treatment. These studies demonstrate central Gi/Go activity mediates i.c.v. N/OFQ's cardiovascular depressor function. Alternatively, central Gz (inhibitory) and Gq (stimulatory) activity differentially modulates AVP release to control the pattern of diuresis to i.c.v. N/OFQ. These findings highlight the novel selective central G-subunit protein mediated control of cardiovascular versus renal excretory function.