Tuberoinfundibular peptide of 39 residues (TIP39) is a recently discovered neuropeptide identified on the basis of its ability to activate the parathyroid hormone-2 (PTH2) receptor, and is thought to be the brain PTH2 receptor's endogenous ligand. The PTH2 receptor is highly expressed in the hypothalamus, suggesting a role in the modulation of neuroendocrinological functions. PTH-related protein (PTHrP), which also belongs to the PTH-related peptides family, stimulates arginine vasopressin (AVP) release. In the present study, therefore, we investigated the effect of centrally administered TIP39 on AVP release in conscious rats. Intracerebroventricular (icv) administration of TIP39 (10-500 pmol/rat) significantly suppressed the plasma AVP concentration in dehydrated rats, and the maximum effect was obtained 5 min after administration (dehydration with 100 pmol/rat TIP39, 4.32 ± 1.17 pg/ml vs. control, 8.21 ± 0.70 pg/ml). The plasma AVP increase in response to either hyperosmolality [intraperitoneal (ip) injection of hypertonic saline (HS) (600 mosmol/kg)] or hypovolemia [ip injection of polyethylene glycol (PEG)] was also significantly attenuated by an icv injection of TIP39 (HS with 100 pmol/rat TIP39, 2.65 ± 0.52 pg/ml vs. HS alone, 4.69 ± 0.80 pg/ml; PEG with 100 pmol/rat TIP39, 4.10 ± 0.79 pg/ml vs. PEG alone, 6.19 ± 0.34 pg/ml). Treatment with naloxone [1.5 mg/rat, subcutaneous injection], a non-selective opioid receptor antagonist, significantly reversed the inhibitory effects of TIP39 on AVP release. These results suggest that central TIP39 plays an inhibitory role in the osmoregulation and baroregulation of AVP release, and that intrinsic opioid systems are involved in its mechanism.