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Endocrinology, doi:10.1210/en.2002-0017
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Endocrinology Vol. 144, No. 7 2791-2796
Copyright © 2003 by The Endocrine Society

Centrally Administered Tuberoinfundibular Peptide of 39 Residues Inhibits Arginine Vasopressin Release in Conscious Rats

Yoshihisa Sugimura, Takashi Murase, Seiji Ishizaki, Kazushige Tachikawa, Hiroshi Arima, Yoshitaka Miura, Ted B. Usdin and Yutaka Oiso

Department of Internal Medicine (Y.S., S.I., K.T., H.A., Y.M., Y.O.), Nagoya University, Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Research Institute of Environmental Medicine (T.M.), Nagoya University, Nagoya, Aichi 464-8601, Japan; and Laboratory of Genetics (T.B.U.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Takashi Murase, M.D., Ph.D., Department of Teratology and Genetics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: tmurase{at}riem.nagoya-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Tuberoinfundibular peptide of 39 residues (TIP39) is a recently discovered neuropeptide identified on the basis of its ability to activate the PTH2 receptor, and it 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. 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 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 [ip injection of hypertonic saline (HS), 600 mosmol/kg] or hypovolemia [ip injection of polyethylene glycol (PEG)] was also significantly attenuated by an intracerebroventricular 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, sc injection], a nonselective 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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TUBEROINFUNDIBULAR PEPTIDE OF 39 residues (TIP39), a 39-amino-acid peptide, is a recently discovered neuropeptide that was purified from bovine hypothalamus on the basis of its ability to activate the PTH2 receptor (1). The PTH2 receptor and TIP39 form part of an extended family of related receptors and related ligands that also includes the PTH1 receptor, PTH3 receptor, PTH, and PTHrP. The PTH2 receptor shares about 50% amino acid sequence identity with the PTH1 receptor (2). PTH activates both PTH1 and PTH2 receptors, whereas PTHrP activates the PTH1 receptor only (2). TIP39 potently activates the PTH2 receptor but does not activate the PTH1 receptor (3, 4). A PTH3 receptor has been identified only in zebrafish (5). Although the PTH2 receptor is present at maximum levels in the brain (6, 7, 8), hardly any PTH is found in the brain (9). Moreover, TIP39 activates rat PTH2 receptor more strongly than PTH (10). Therefore, TIP39 is thought to be the endogenous selective ligand of the brain PTH2 receptor.

The physiological role of the TIP39-PTH2 receptor system remains to be elucidated. TIP39 and PTH2 receptor are not considered to play an important role in calcium metabolism, which is mediated mainly by PTH1 receptor, on which TIP39 has little or no effect, and the PTH2 receptor is detected only within a very small number of cells in bone and kidney (6). PTH2 receptor messenger RNA is most abundantly expressed in the brain and at somewhat lower levels in the pancreas, placenta, and lung, suggesting that PTH2 receptor plays its main role in the central nervous system (8). In the rat brain, both immunohistochemistry and in situ hybridization histochemistry revealed that the expression of the PTH2 receptor is high in the septum and the hypothalamus, particularly in the periventricular and arcuate nuclei (7). Fibers and terminals are strongly labeled by a PTH2 receptor-selective antibody in the median eminence. These findings suggest a role of PTH2 receptor in the neuroendocrine function. It has been recently reported that TIP39 increases the release of corticotropin-releasing factor and LHRH from in vitro hypothalamic explants, and that icv injection of TIP39 increases plasma ACTH and LH in vivo in rats (11). TIP39 has also been reported to potentiate aspects of nociception within the spinal cord (12). In the peripheral tissues, it has been shown that both TIP39 and PTH2 receptor mRNA are expressed in rat renal vessels and that TIP39 exhibits vasodilatative effects (13).

Arginine vasopressin (AVP), an antidiuretic hormone, is synthesized in the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and is transported axonally and stored in the posterior pituitary until it is released into peripheral circulation (14). AVP release is regulated mainly by plasma osmolality, blood volume, and/or blood pressure (15). In addition, there are close neural connections between SON or PVN and other hypothalamic nuclei (16, 17, 18), and AVP release is regulated by other neuronal systems such as opioid neurons (19, 20, 21, 22). PTH2 receptor is relatively abundant in the arcuate nucleus, which has a significant input to the PVN and SON. The distribution of the PTH2 receptor in the hypothalamus suggests a role of TIP39 involving water homeostasis and AVP release. Moreover, PTHrP, which also belongs to the PTH-related peptides family, has been reported to stimulate AVP release in vivo and in vitro from SON via a novel receptor (23, 24).

In the present study, therefore, to elucidate the role of TIP39 in the regulation of the hypothalamus-neurohypophysial system, we examined the effect of a central injection of TIP39 on AVP release in conscious rats. We showed here that TIP39 markedly suppressed AVP release induced by dehydration, hyperosmolality, or hypovolemia. Furthermore, we evaluated the effects of naloxone, a nonselective opioid receptor antagonist, on the AVP release-inhibitory action of TIP39 to determine whether the intrinsic opioid systems are involved in the mechanism.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Male Sprague Dawley rats [body weight (BW), 250–300 g; Chubu Science Materials, Nagoya, Japan] were housed in a colony room maintained at 23 C with lights on from 0900–2100 h. Rats had ad libitum access to standard raw chow and tap water until immediately before each experiment. Five days before the experiments, the rats were anesthetized by an ip injection of sodium pentobarbital (50 mg/kg BW), and a 21-gauge stainless steel cannula was inserted stereotaxically into the right lateral ventricle for an intracerebroventricular (icv) injection. The stereotaxic coordinates were 0.8 mm posterior to the bregma, 1.4 mm lateral to the midline, and 4.0 mm below the surface of the skull. The cannula was fixed with dental cement and anchored to the skull with two jeweler’s screws. Appropriate placement of the icv cannula was verified by an icv injection of dye after decapitation. All experiments were performed on conscious, unrestrained rats between 0900 and 1130 h. All procedures were performed in accordance with the institutional guidelines for animal care at Nagoya University School of Medicine.

All icv injections were in a volume of 10 µl infused in 1 min. Bovine TIP39 (AnaSpec, Inc., San Jose, CA) was dissolved in isotonic saline and injected icv. An equal volume of vehicle was injected as the control. Naloxone hydrochloride (Sigma, St. Louis, MO) was dissolved in isotonic saline and injected sc at a dose of 1.5 mg/rat in a volume of 0.25 ml. The ip injection in all experiments was performed at a volume of 2% BW.

Experiment 1: effects of icv TIP39 on basal AVP release
Rats were injected icv with TIP39 (100 pmol/rat) or vehicle and decapitated 5 or 15 min after injection. The dose of TIP39 was chosen considering our previous study (25).

Experiment 2: time-course effects of icv TIP39 on AVP release induced by dehydration
All rats were deprived of water for 48 h, then injected icv with TIP39 (100 pmol/rat) or vehicle, and decapitated 5, 10, or 20 min after injection.

Experiment 3: dose-response effects of icv TIP39 on AVP release induced by dehydration
All rats except for a baseline group were deprived of water for 48 h. TIP39 (1–500 pmol/rat) or vehicle was injected icv to water-deprived rats, and rats were decapitated 5 min after injection.

Experiment 4: hyperosmolar and hypovolemic stimulation
Rats were injected ip with hypertonic saline (HS; 600 mosmol/kg) 30 min before decapitation. TIP39 (100 pmol/rat) or vehicle was injected icv, and rats were decapitated 5 min after the injection. Polyethylene glycol (PEG) reduces plasma volume without altering plasma osmolality or sodium (26, 27). Rats were injected ip with PEG (molecular weight, 3000; Wako Pure Chemical Industries, Ltd., Osaka, Japan) dissolved in isotonic saline (20% wt/vol) 90 min before decapitation. TIP39 (100 pmol/rat) or vehicle was injected icv, and rats were decapitated 5 min after the injection. Control rats were injected with isotonic saline ip, and then isotonic saline was injected icv. The time point of the ip injection used in the analysis was selected in the light of previous studies (27, 28).

Experiment 5: effects of sc naloxone on AVP release induced by dehydration
All rats were deprived of water for 48 h. Rats were injected sc with naloxone (1.5 mg/rat) or vehicle 35 min before decapitation. TIP39 (100 pmol/rat) or vehicle was injected icv, and rats were decapitated 5 min after injection. The dose of naloxone was chosen considering the previous reports (28, 29).

Experiment 6: effects of icv TIP (7–39) on AVP release induced by dehydration
To demonstrate the receptor and/or peptide specificity of the effect of TIP39, we evaluated the effects of TIP (7–39), a truncated form of TIP39 that is inactive at PTH2 receptor (30), on AVP release. All rats were deprived of water for 48 h. TIP (7–39), 10–500 pmol/rat or vehicle, was injected icv, and rats were decapitated 5 min after injection.

Experiment 7: effects of icv TIP39 on blood pressure
Rats were reanesthetized on the day before the experiment, and a polyethylene cannula was implanted into the right carotid artery for blood pressure measurement. TIP39 (100 pmol/rat) was injected icv, and arterial blood pressure was measured with a blood pressure transducer (Gould, Oxnard, CA) connected to the implanted cannula. Baseline values were recorded for 10 min before injection. Arterial blood pressure was recorded continuously for 20 min after icv injection.

Measurement of plasma AVP, Na+, and total protein (TP)
After decapitation, trunk blood was collected into chilled tubes containing EDTA (potassium salt). After immediate separation, plasma AVP was extracted through a Sep-Pak C18 Cartridge (Waters Associates Inc., Milford, MA) and measured using a RIA kit (AVP-RIA kit provided by Mitsubishi Chemical Co., Ltd., Tokyo, Japan) as previously described (28). The sensitivity of the assay for AVP was 0.063 pg/tube (0.197 pg/ml in plasma samples), with less than 0.01% cross-reactivity with oxytocin (26). Plasma sodium was measured using an autoanalyzer (Hitachi, Tokyo, Japan) for estimation of the change in plasma osmolality. TP was also measured by the autoanalyzer for estimation of the change in plasma volume.

Statistics
Results were expressed as mean ± SEM. Multiple comparisons were evaluated by one-way or two-way ANOVA followed by Fisher’s projected least significant difference (PLSD) test. Differences were considered statistically significant at P value less than 0.05. We used five rats for each group in all experiments, except for a blood pressure measurement where three rats were used for each group.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1: effects of icv TIP39 on basal AVP release
TIP39 (100 pmol/rat) significantly decreased plasma AVP levels 5 min after injection (0.70 ± 0.09 pg/ml vs. control, 1.24 ± 0.13 pg/ml; P < 0.05) at baseline. There was no significant decrease in plasma AVP 15 min after injection of TIP39 compared with control group. TIP39 did not significantly change plasma Na+ and plasma TP (data not shown).

Experiment 2: time-course effects of icv TIP39 on AVP release induced by dehydration
TIP39 (100 pmol/rat) injected icv significantly suppressed the dehydration-induced plasma AVP increase with its maximum effect occurring 5 min after injection (4.32 ± 1.17 pg/ml, vs. control, 8.21 ± 0.70 pg/ml; P < 0.05; Fig. 1Go).



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  		Figure 1. Time-course effects of TIP39 icv on AVP release. All rats were deprived of water for 48 h. TIP39 (100 pmol/rat; {circ}) or vehicle ({bullet}) was injected icv, and rats were decapitated 5, 10, or 20 min after injection. AVP was extracted from plasma and quantified by RIA. Values are shown as mean ± SEM (n = 5). Two-way ANOVA; P = 0.0136. *, P < 0.05 compared with control by Fisher’s PLSD test.

 
Experiment 3: dose-response effects of icv TIP39 on AVP release induced by dehydration
After water deprivation for 48 h, plasma Na+ and TP significantly increased compared with baseline group, indicating an increase in plasma osmolality and the decrease in plasma volume, respectively (Table 1Go). TIP39 (10–500 pmol/rat) injected icv significantly suppressed the dehydration-induced plasma AVP increase (TIP39 100 pmol/rat, 4.64 ± 0.31 pg/ml, vs. control, 6.87 ± 0.67 pg/ml; P < 0.05; Fig. 2Go).


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  		Table 1. Effect of plasma Na+ and TP levels in each experiment

 


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  		Figure 2. Dose-response effects of TIP39 icv on AVP release. All rats except for a baseline group were deprived of water for 48 h. TIP39 (1–500 pmol/rat) or vehicle was injected icv to water-deprived rats, and rats were decapitated 5 min after injection. AVP was extracted from plasma and quantified by RIA. Values are shown as mean ± SEM (n = 5). One-way ANOVA; P < 0.0001. #, P < 0.05 compared with baseline; *, P < 0.05 compared with saline by Fisher’s PLSD test.

 
Experiment 4: hyperosmolar and hypovolemic stimulation
After ip injection of HS, plasma Na increased from 139.0 ± 0.7 mEq/liter in control rats to 141.8 ± 0.8 mEq/liter (Table 1Go). TIP39 (100 pmol/rat) injected icv significantly suppressed osmotically increased plasma AVP 5 min after injection (2.65 ± 0.52 pg/ml, vs. control 4.69 ± 0.80 pg/ml; P < 0.05; Fig. 3Go). After ip injection of PEG, plasma TP increased from 5.76 ± 0.09 g/dl in control rats to 6.55 ± 0.19 g/dl, whereas plasma Na+ in the two groups was not significantly affected. TIP39 (100 pmol/ rat) injected icv significantly suppressed the hypovolemia-induced increase in plasma AVP (4.10 ± 0.79 pg/ml, vs. control, 6.19 ± 0.34 pg/ml; P < 0.01; Fig. 3Go).



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  		Figure 3. Effects of TIP39 icv on AVP release induced by hyperosmolality or hypovolemia. Rats were injected ip with HS (600 mosmol/kg; 2% BW) 30 min before they were killed by decapitation. TIP39 (100 pmol/rat) or vehicle was injected icv 5 min before decapitation. Rats were injected ip with PEG (20% wt/vol; 2% BW) 90 min before decapitation. TIP39 (100 pmol/rat) or vehicle was injected icv 5 min before decapitation. Control rats were injected with isotonic saline ip, and then isotonic saline was injected icv. AVP was extracted from plasma and quantified by RIA. Values are shown as mean ± SEM (n = 5). One-way ANOVA; P < 0.0001. *, P < 0.05 by Fisher’s PLSD test.

 
Experiment 5: effects of sc naloxone on AVP release induced by dehydration
Treatment with naloxone significantly reversed the inhibitory effect of TIP39 (icv) on dehydration-induced AVP release, whereas naloxone alone did not significantly alter the plasma AVP level (Fig. 4Go).



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  		Figure 4. Effects of naloxone on icv TIP39-induced inhibition of AVP release due to dehydration. Rats were deprived of water for 48 h. TIP39 (100 pmol/rat) or vehicle was injected icv 5 min before decapitation. Naloxone (NAL; 1.5 mg/rat) or vehicle was injected sc 30 min before icv injection of TIP39. Control rats were injected with isotonic saline sc, and then isotonic saline was injected icv. AVP was extracted from plasma and quantified by RIA. One-way ANOVA; P < 0.0001. *, P < 0.05 by Fisher’s PLSD test.

 
Experiment 6: effects of icv TIP (7–39) on AVP release induced by dehydration
Intracerebroventricular injection of TIP (7–39) over the range from 10–500 pmol/rat had no significant effects on dehydration-induced AVP release (Fig. 5Go). There were no significant changes in plasma Na+ and TP after injection of TIP (7–39) (data not shown).



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  		Figure 5. Effects of TIP (7–39) icv on AVP release. All rats were deprived of water for 48 h. TIP (7–39) (10–500 pmol/rat) or vehicle was injected icv, and rats were decapitated 5 min after injection. AVP was extracted from plasma and quantified by RIA. Values are shown as mean ± SEM (n = 5). One-way ANOVA; P = 0.3113. There were no significant differences among each group.

 
Experiment 7: effects of TIP39 icv on blood pressure
TIP39 (100 pmol/rat) injected icv gradually decreased mean arterial pressure, and significant changes were seen 20 min after injection (Table 2Go).


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  		Table 2. Effect of TIP39 on mean arterial blood pressure

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we investigated the effect of centrally administered TIP39 on AVP release in conscious rats. We here showed that the icv injection of TIP39 markedly suppressed the AVP release induced by dehydration, hyperosmolality, or hypovolemia, and also showed that treatment with naloxone significantly reversed the inhibitory effects of TIP39 on AVP release. This is the first report demonstrating the effect of TIP39 on AVP release in vivo; our data suggest that TIP39 plays an inhibitory role in the regulation of AVP release, and that the intrinsic opioid systems are involved in the mechanism.

This inhibitory effect cannot be attributed to a decrease in the level of osmotic or hypovolemic stimulation because plasma Na+ and plasma TP were not affected by the icv injection of TIP39. In addition, we showed that an icv injection of TIP39 produced a fall in blood pressure, which is well known to stimulate AVP secretion. Therefore, the inhibitory effect of TIP39 was not based on the change in blood pressure. Taken together, these results suggest that TIP39 inhibits AVP release by central action, not by causing hemodynamic or osmotic change.

Although the exact sites of action of TIP39 injected icv were not obvious from the present study, it suppressed AVP secretion elevated by both hyperosmolar and hypovolemic stimuli, indicating that TIP39 has an effect on the efferent pathway for the secretion of AVP, which reflects integrated inputs from osmoreceptor and baroreceptor systems. In addition, drugs injected icv can readily permeate the hypothalamus yet not reach the posterior pituitary (31). These results suggest that endogenous TIP39 may thus play a functional role in the regulation of AVP secretion at the level of the hypothalamus.

Because TIP39 is a selective agonist for the brain PTH2 receptor, it is reasonable to think that TIP39 exerts the AVP release-inhibitory action via PTH2 receptors. To demonstrate the receptor and/or peptide specificity of the effect of TIP39, we evaluated the effects of TIP (7–39), a truncated form of TIP39, on AVP release. TIP (7–39) had no significant effects on dehydration-induced AVP release. TIP39 is a potent agonist for the PTH2 receptor, whereas TIP (7–39) is almost inactive at PTH2 receptor (30). Therefore, these results suggest that the AVP release-suppressing effect of TIP39 may be mediated by PTH2 receptor. However, it has been reported that PTH, which also can activate PTH2 receptor, has little effect on AVP release either in vivo or in vitro (23, 24). The differences in both potency and efficacy between TIP39 and PTH for activation of the rat PTH2 receptor could explain these findings; TIP39 is much more potent than PTH in its activity to stimulate cAMP production via rat PTH2 receptor (1, 10, 32).

PTH2 receptor has been reported to be abundant in the hypothalamus, particularly in the periventricular and arcuate nuclei by immunohistochemistry and in situ hybridization histochemistry, whereas its expression is weak in the SON or PVN where AVP is synthesized (6). It seems, therefore, more likely that TIP39 exerts its AVP release-inhibitory effect by acting through other hypothalamic nuclei, such as the arcuate nuclei, rather than acting directly on SON or PVN. In the arcuate nucleus, for example, many opioid neurons are known to exist (33). There is a great deal of evidence showing that opioid systems are involved in the regulation of AVP release (19, 20, 21, 22). Most studies demonstrate that opioids play an inhibitory role in the regulation of AVP release, and that such a release in response to hyperosmolality or hypovolemia is attenuated by opioid agonists (19, 28). Because there are close neural connections between arcuate nuclei and PVN or SON (16, 17, 18), these findings lead us to speculate that TIP39 exerts its suppressive effects on AVP release by activating opioid neurons in the arcuate nuclei via PTH2 receptors there. To test this hypothesis, we evaluated the effects of naloxone, an opioid receptor antagonist, on the AVP release-suppressing action of TIP39. Results showed that the injection of naloxone, which crosses the blood-brain barrier (34) and has an affinity for all major opioid receptor subtypes, significantly reversed the inhibitory effect of TIP39 on AVP release. These results suggest that intrinsic opioid systems are involved in the AVP release-suppressing effect of TIP39. As shown in the time-course study, not only was a significant decrease in plasma AVP observed as early as 5 min after injection, but the effects did not last long. The immediate and brief time-course was similar to that of neuropeptide FF, which is an endogenous modulator of opioid systems and inhibits AVP release by icv injection in conscious rats (35). Because the action of TIP39 was very fast and brief, TIP39 may play an important role in the dynamic regulation of AVP release.

Interestingly, Ward et al. (11) recently reported that TIP39 increases AVP release in the hypothalamic explants in vitro, which seems to be incompatible with our results showing that TIP39 suppresses AVP release in vivo. It is unclear what caused the discrepancy between their results and ours, but one possibility is that in the in vitro hypothalamic explants in which no valid neural connections may exist between PVN or SON and other hypothalamic nuclei in the different levels of the brain, the effect of TIP39 may only be exhibited by its direct action on the PVN or SON which would stimulate AVP release, although the expression of PTH2 receptor is weak in those nuclei. On the other hand, in the rat in vivo, icv-injected TIP39 may act on the other hypothalamic nuclei including arcuate nuclei where the expression of PTH2 receptor is abundant, and may suppress AVP release via activation of the AVP release-inhibitory neurons such as opioid neurons, overcoming the direct AVP release-stimulating effect of TIP39. It has been reported that PTHrP stimulates AVP release in vivo and in vitro from SON via a novel receptor that is different from both the PTH1 and PTH2 receptors (23, 24). Thus, it may also be possible that TIP39 stimulates AVP release via this unknown receptor in SON.

Although we clearly showed that TIP39 had inhibitory effects on AVP release in the present study, the physiological relevance of the AVP release-suppressive effect of TIP39 has not been proven yet. The decrease in plasma AVP levels after injection of TIP39 is transient and still at a level at which AVP can exert its biological effects. However, when injected at baseline without dehydration, TIP39 significantly decreased AVP levels from 1.24–0.70 pg/ml. The decrease was approximately 44%, which is similar to the results obtained in Fig. 1Go (47.4%) and Fig. 2Go (32.7%). These results led us to the assumption that TIP39 may decrease AVP levels similarly in various conditions. Therefore, although the AVP level after TIP39 injection is still high enough to exert its biological effect in the condition that the AVP level is markedly elevated, such as in the dehydrated state, it would also be possible that the decrease in AVP level after TIP39 injection could attenuate the biological effect of AVP in the condition that plasma AVP level is not so high. In addition, we examined the effect of a single injection of TIP39 in the present study. If endogenous TIP39 would be released continuously or repeatedly, the effects could be different. Little is known about the regulation of TIP39 release or synthesis, and further studies are required to clarify this point.

In conclusion, results of the present study suggest that central TIP39 plays an inhibitory role in the osmoregulation and baroregulation of AVP release, possibly via PTH2 receptors in the hypothalamus, and that intrinsic opioid systems are involved in the action of TIP39.


   Footnotes
 
Abbreviations: AVP, Arginine vasopressin; BW, body weight; HS, hypertonic saline; icv, intracerebroventricular; PEG, polyethylene glycol; PLSD, projected least significant difference; PVN, paraventricular nucleus; SON, supraoptic nucleus; TIP39, tuberoinfundibular peptide of 39 residues; TP, total protein.

Received November 8, 2002.

Accepted for publication March 31, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Usdin TB, Hoare SR, Wang T, Mezey E, Kowalak JA 1999 TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus. Nat Neurosci 2:941–943[CrossRef][Medline]
  2. Usdin TB, Gruber C, Bonner TI 1995 Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2 receptor. J Biol Chem 270:15455–15458[Abstract/Free Full Text]
  3. Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski Jr LF, Hock J, Potts Jr JT, Kronenberg HM, Segre GE 1991 A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024–1026[Abstract/Free Full Text]
  4. Hoare SR, Usdin TB 2001 Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors. Curr Pharm Des 7:689–713[CrossRef][Medline]
  5. Rubin DA, Juppner H 1999 Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. J Biol Chem 274:28185–28190[Abstract/Free Full Text]
  6. Usdin TB, Hilton J, Vertesi T, Harta G, Segre G, Mezey E 1999 Distribution of the parathyroid hormone 2 receptor in rat: immunolocalization reveals expression by several endocrine cells. Endocrinology 140:3363–3371[Abstract/Free Full Text]
  7. Wang T, Palkovits M, Rusnak M, Mezey E, Usdin TB 2000 Distribution of parathyroid hormone-2 receptor-like immunoreactivity and messenger RNA in the rat nervous system. Neuroscience 100:629–649[CrossRef][Medline]
  8. Usdin TB, Bonner TI, Harta G, Mezey E 1996 Distribution of parathyroid hormone-2 receptor messenger ribonucleic acid in rat. Endocrinology 137:4285–4297[Abstract]
  9. Usdin TB 1997 Evidence for a parathyroid hormone-2 receptor selective ligand in the hypothalamus. Endocrinology 138:831–834[Abstract/Free Full Text]
  10. Hoare SR, Bonner TI, Usdin TB 1999 Comparison of rat and human parathyroid hormone 2 (PTH2) receptor activation: PTH is a low potency partial agonist at the rat PTH2 receptor. Endocrinology 140:4419–4425[Abstract/Free Full Text]
  11. Ward HL, Small CJ, Murphy KG, Kennedy AR, Ghatei MA, Bloom SR 2001 The actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes. Endocrinology 142:3451–3456[Abstract/Free Full Text]
  12. Dobolyi A, Ueda H, Uchida H, Palkovits M, Usdin TB 2002 Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception. Proc Natl Acad Sci USA 99:1651–1656[Abstract/Free Full Text]
  13. Eichinger A, Fiaschi-Taesch N, Massfelder T, Fritsch S, Barthelmebs M, Helwig JJ 2002 Transcript expression of the tuberoinfundibular peptide (TIP)39/PTH2 receptor system and non-PTH1 receptor-mediated tonic effects of TIP39 and other PTH2 receptor ligands in renal vessels. Endocrinology 143:3036–3043[Abstract/Free Full Text]
  14. Bisset GW, Chowdrey HS 1988 Control of release of vasopressin by neuroendocrine reflexes. Q J Exp Physiol 73:811–872[Free Full Text]
  15. Robertson GL 1976 The regulation of vasopressin function in health and disease. Recent Prog Horm Res 33:333–385
  16. Baker RA, Herkenham M 1995 Arcuate nucleus neurons that project to the hypothalamic paraventricular nucleus: neuropeptidergic identity and consequences of adrenalectomy on mRNA levels in the rat. J Comp Neurol 358:518–530[CrossRef][Medline]
  17. Bell ME, Bhatnagar S, Akana SF, Choi S, Dallman MF 2000 Disruption of arcuate/paraventricular nucleus connections changes body energy balance and response to acute stress. J Neurosci 20:6707–6713[Abstract/Free Full Text]
  18. Kawano H, Masuko S 2000 ß-Endorphin-, adrenocorticotrophic hormone-, and neuropeptide Y-containing projection fibers from the arcuate hypothalamic nucleus make synaptic contacts on to nucleus preopticus medianus neurons projecting to the paraventricular hypothalamic nucleus in the rat. Neuroscience 98:555–565[CrossRef][Medline]
  19. Haaf JA, Maigret C, Andringa-Bakker EA, van Wimersma Greidanus TB 1987 Dynorphin-(1–13) is a potent in vivo suppressor of vasopressin levels in the rat. Acta Endocrinol (Copenh) 114:96–101
  20. Summy-Long JY, Rosella-Dampman LM, McLemore GL, Koehler E 1990 {kappa}-Opiate receptors inhibit release of oxytocin from the magnocellular system during dehydration. Neuroendocrinology 51:376–384[Medline]
  21. Van de Heijning BJ, Koekkoek-Van den Herik I, Van Wimersma Greidanus TB 1991 The opioid receptor subtypes µ and {kappa}, but not {delta}, are involved in the control of the vasopressin and oxytocin release in the rat. Eur J Pharmacol 209:199–206[CrossRef][Medline]
  22. Van de Heijning BJ, Koekkoek-Van den Herik I, Maigret C, Van Wimersma Greidanus TB 1991 Pharmacological assessment of the site of action of opioids on the release of vasopressin and oxytocin in the rat. Eur J Pharmacol 197:175–180[CrossRef][Medline]
  23. Yamamoto S, Morimoto I, Yanagihara N, Zeki K, Fujihira T, Izumi F, Yamashita H, Eto S 1997 Parathyroid hormone-related peptide-(1–34) [PTHrP-(1–34)] induces vasopressin release from the rat supraoptic nucleus in vitro through a novel receptor distinct from a type I or type II PTH/PTHrP receptor. Endocrinology 138:2066–2072[Abstract/Free Full Text]
  24. Yamamoto S, Morimoto I, Zeki K, Ueta Y, Yamashita H, Kannan H, Eto S 1998 Centrally administered parathyroid hormone (PTH)-related protein(1–34) but not PTH(1–34) stimulates arginine-vasopressin secretion and its messenger ribonucleic acid expression in supraoptic nucleus of the conscious rats. Endocrinology 139:383–388[Abstract/Free Full Text]
  25. Ishizaki S, Murase T, Sugimura Y, Kakiya S, Yokoi H, Tachikawa K, Arima H, Miura Y, Oiso Y 2002 Role of ghrelin in the regulation of vasopressin release in conscious rats. Endocrinology 143:1589–1593[Abstract/Free Full Text]
  26. Dunn FL, Brennan TJ, Nelson AE, Robertson GL 1973 The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J Clin Invest 52:3212–3219
  27. Kakiya S, Murase T, Arima H, Yokoi H, Iwasaki Y, Miura Y, Oiso Y 2000 Role of endogenous nociceptin in the regulation of arginine vasopressin release in conscious rats. Endocrinology 141:4466–4471[Abstract/Free Full Text]
  28. Oiso Y, Iwasaki Y, Kondo K, Takatsuki K, Tomita A 1988 Effect of the opioid {kappa}-receptor agonist U50488H on the secretion of arginine vasopressin. Study on the mechanism of U50488H-induced diuresis. Neuroendocrinology 48:658–662[Medline]
  29. Doi N, Brown CH, Cohen HD, Leng G, Russell JA 2001 Effects of the endogenous opioid peptide, endomorphin 1, on supraoptic nucleus oxytocin and vasopressin neurones in vivo and in vitro. Br J Pharmacol 132:1136–1144[CrossRef][Medline]
  30. Hoare SR, Clark JA, Usdin TB 2000 Molecular determinants of tuberoinfundibular peptide of 39 residues (TIP39) selectivity for the parathyroid hormone-2 (PTH2) receptor. N-terminal truncation of TIP39 reverses PTH2 receptor/PTH1 receptor binding selectivity. J Biol Chem 275:27274–27283[Abstract/Free Full Text]
  31. Feldberg W 1976 The ventral surface of the brain stem: a scarcely explored region of pharmacological sensitivity. Neuroscience 1:427–441[CrossRef][Medline]
  32. Usdin TB 2000 The PTH2 receptor and TIP39: a new peptide-receptor system. Trends Pharmacol Sci 21:128–130[CrossRef][Medline]
  33. Lantos TA, Gorcs TJ, Palkovits M 1995 Immunohistochemical mapping of neuropeptides in the premamillary region of the hypothalamus in rats. Brain Res Brain Res Rev 20:209–249[CrossRef][Medline]
  34. Berkowitz BA, Ngai SH, Hempstead J, Spector S 1975 Disposition of naloxone: use of a new radioimmunoassay. J Pharmacol Exp Ther 195:499–504[Abstract/Free Full Text]
  35. Arima H, Murase T, Kondo K, Iwasaki Y, Oiso Y 1996 Centrally administered neuropeptide FF inhibits arginine vasopressin release in conscious rats. Endocrinology 137:1523–1529[Abstract]



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