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Role of Endogenous Nociceptin in the Regulation of Arginine Vasopressin Release in Conscious Rats

First Department of Internal Medicine (S.K., T.M., H.A., H.Y., Y.M., Y.O.), Department of Clinical Laboratory Medicine (Y.I.), Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550, Japan

Address all correspondence and requests for reprints to: Satoshi Kakiya, First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: skakiya{at}med.nagoya-u.ac.jp

	Abstract

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The effects of central administration of the opioid-like peptide nociceptin (also known as orphanin FQ) were investigated on the secretion of arginine vasopressin (AVP) in response to dehydration and hyperosmolar or hypovolemic stimulation in conscious rats. Intracerebroventricular (icv) administration of nociceptin suppressed plasma AVP concentration in a dose-dependent manner (0.1–10 µg/rat) in dehydrated rats, and the maximum effect was obtained 10 min after the administration (dehydration with 10 µg/rat nociceptin, 3.11 ± 0.27 pg/ml vs. control, 10.32 ± 0.96 pg/ml). The plasma AVP increase in response to either hyperosmolality [ip injection of hypertonic saline (HS) (600 mosml/kg)] or hypovolemia [ip injection of polyethylene glycol (PEG)] was also significantly blunted when nociceptin was injected icv (HS with 10 µg/rat nociceptin, 1.16 ± 0.09 pg/ml vs. control, 1.82 ± 0.30 pg/ml; PEG with 10 µg/rat nociceptin, 0.91 ± 0.16 pg/ml vs. control, 2.41 ± 0.26 pg/ml). Pretreatment with a selective opioid -receptor antagonist, nor-binaltorphimine (1 µg/rat, icv) or naloxone (2.5 mg/rat, sc injection) did not reverse the inhibitory effects of nociceptin on AVP release. Moreover, when plasma AVP was suppressed by acute water loading, immunoneutralization of endogenous nociceptin by antinociceptin-antiserum icv significantly reversed the suppression (0.57 ± 0.12 pg/ml vs. control, 0.25 ± 0.04 pg/ml). These results suggest that central nociceptin is physiologically involved in the control of AVP release through an inhibitory action.

	Introduction

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IN ADDITION to the classical opioid receptor subtypes (µ, , and ), complementary DNA expression cloning techniques have been used to isolate and identify a novel opioid receptor referred to as opioid receptor-like 1 (ORL1) (1, 2). Despite its close similarity to µ-, -, and -opioid receptors (1, 2), this receptor does not bind any of the previously identified opioid peptides or ligands (2, 3, 4, 5). The endogenous ligand (with the primary structure Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln) was soon isolated and named nociceptin (6) or orphanin FQ (7), which shares structural homology with the -opioid agonist dynorphin A (6, 7, 8). Despite this resemblance, actions distinctive of the nociceptin systems have been suggested. In previous investigations, nociceptin induced various phenomena, such as hyperalgesia (6, 7), allodynia (9), antagonism to opioid effects (10), analgesia (11), and nociception (6, 7, 12). Recently, nociceptin has also been reported to activate hypothalamic-pituitary-adrenal (HPA) axis (13).

ORL1 transcripts have been shown to be expressed in brain regions known to participate in the regulation of blood pressure as well as fluid and electrolyte balance (e. g. the hypothalamus, amygdala) (14). Previous studies have revealed the distribution of ORL1 receptors and ORL1-containing nerve terminals in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) (14, 15). The parvocellular portion of the PVN also has some nociceptin and nociceptin mes- senger RNA (mRNA)-positive cell bodies (15). Arginine vasopressin (AVP), an antidiuretic hormone, is synthesized in the SON and PVN, transported axonally, and stored in the posterior pituitary until it is released into peripheral circulation (16). AVP exerts diverse effects on various organs via three types of receptors V1a, V1b, and V2. V1a receptors mediate contraction of vascular smooth muscle and stimulation of hepatic gluconeogenesis. V1b receptors stimulate ACTH secretion from the anterior pituitary. V2 receptors in the kidney are responsible for the antidiuretic effect of AVP (17). The expression of the nociceptin receptor and nociceptin precursor mRNA in the hypothalamus suggests that nociceptin may play a role in regulating neurosecretion from SON and PVN. Indeed, previous electrophysiological studies have shown inhibitory actions of nociceptin on AVP neurons in the SON (18, 19, 20). Moreover, nociceptin can cause a rapid diuresis following intracerebroventricular (icv) administration (21). These results suggest that nociceptin is acting at central sites to affect fluid balance and AVP release.

In this study, to elucidate the role of nociceptin in the hypothalamo-neurohypophysial system, we examined the effect of centrally administered nociceptin on AVP release in conscious rats as they were affected by dehydration, hyperosmolality or hypovolemia. In addition, to elucidate the role of endogenous nociceptin in the control of AVP release, an icv injection of the antiserum (As) against nociceptin was performed. Furthermore, to test the possibility that the intrinsic opioid systems are physiologically involved in the action of nociceptin, the effects of the broad opioid antagonist naloxone, or the selective -opioid receptor antagonist nor-binaltorphimine (nor-BNI) (22) on the action of nociceptin were investigated.

	Materials and Methods

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Male Sprague Dawley rats (body weight 250–280 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 lib access to standard rat chow and tap water until immediately before each experiment. Five days before the experiments, the rats were anesthetized by ip injection of sodium pentobarbital (50 mg/kg BW), and a 21-gauge stainless steel cannula was inserted stereotaxically into the right lateral ventricle. 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 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. Nociceptin (Peptide Institute, Osaka, Japan) was dissolved in isotonic saline and injected icv. An equal volume of vehicle was injected as the control. The injection dose level of nociceptin was based on previous studies (21). Dynorphin A (Peptide Institute) was dissolved in isotonic saline and injected icv at a dose of 10 µg/rat (21). Naloxone hydrochloride (Sigma, St. Louis, MO) was dissolved in isotonic saline and injected sc at a dose of 2.5 mg/rat in a volume of 0.25 ml. Nor-BNI (1 µg/rat, Sigma) was dissolved in isotonic saline and administered icv. The dose level and time course for the nalxone and nor-BNI injection were based on previous studies (21, 23). The ip injection in all experiments was performed at a volume of 2% of BW.

Exp 1a: time-course effects of icv nociceptin on AVP release induced by dehydration
All rats were deprived of water for 48 h. Rats were injected icv with nociceptin (10 µg/rat) or vehicle and decapitated 10, 20, or 30 min after the injection.

Exp 1b: dose-response effects of icv nociceptin on AVP release induced by dehydration
All rats were deprived of water for 48 h. Nociceptin (0.1–10 µg/rat) or vehicle was injected icv and rats were decapitated 10 min after the injection.

Exp 2: hyperosmolar and hypovolemic stimulation
Rats were injected ip with hypertonic saline (HS) (600 mosml/kg) 30 min before decapitation. Nociceptin (10 µg/rat) or vehicle was injected icv, and rats were decapitated 10 min after the injection. Polyethylene glycol (PEG) reduces plasma volume without altering plasma osmolality and sodium (Na⁺) (23, 24). 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. Nociceptin (10 µg/rat) or vehicle was injected icv, and rats were decapitated 10 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 consideration of previous studies (23, 25).

Exp 3: effects of antagonist on icv nociceptin-induced inhibition on AVP release due to dehydration
All rats were deprived of water for 48 h. Nociceptin (10 µg/rat) or dynorphin A (10 µg/rat) was injected icv and rats were decapitated 10 min after the injection. Nor-BNI (1 µg/rat) or isotonic saline was injected icv 10 min before the icv injection of nociceptin or dynorphin A. Naloxone (2.5 mg/rat) was injected sc 35 min before the icv injection of nociceptin. Control rats were injected with isotonic saline icv.

Exp 4: effects of icv injection of antinociceptin-As on water loading-induced suppression of plasma AVP
Acute water loading was performed by oral administration (po) of water (5 ml/100 g BW) through a flexible stomach tube and rats were decapitated after 60 min. Antinociceptin-As (Yanaihara Institute Inc., Shizuoka, Japan) or normal rabbit serum (NRS) (Chemicon International Inc., Temecula, CA) was injected icv in a volume of 10 µl at 15 min after water loading. Control rats for the oral water administration were decapitated without any treatment. The antinociceptin-As specifically recognizes nociceptin and shows no cross-reactivity with dynorphin A or ß-endorphin according to the manufacturer^’s instructions.

Plasma AVP, Na+ and total protein (TP) measurement
Immediately following decapitation, trunk blood was collected in a tube-containing EDTA for the determination of plasma AVP, Na⁺, and TP. After immediate separation, plasma AVP was extracted through a Sep-pak C18 cartridge (Waters Associates Inc., Milford, MA) and measured using a RIA kit (provided by Mitsubishi Chemical Co., Ltd., Tokyo, Japan). The sensitivity of the assay for AVP was 0.063 pg/tube, with less than 0.01% cross-reactivity with oxytocin (24). Plasma Na⁺ 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
All results are expressed as mean ± SEM. Multiple comparisons were evaluated by a one-way ANOVA followed by Fisher PLSD test. Differences were considered statistically significant at P < 0.05. The group size was six in all experiments.

	Results

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Exp 1a: time-course effects of icv nociceptin on AVP release induced by dehydration
Nociceptin (10 µg/rat) injected icv significantly suppressed the dehydration-increased plasma AVP with the maximum effect 10 min after the injection (3.11 ± 0.27 pg/ml vs. control, 10.32 ± 0.96 pg/ml; P < 0.01, Fig. 1A).

View larger version (19K): [in this window] [in a new window]   Figure 1. Effects of nociceptin (icv) on AVP release. All rats were deprived of water for 48 h. A, Time-course effects. Nociceptin (10 µg/rat; ) or vehicle (•) was injected icv, and rats were decapitated 10, 20, or 30 min after the injection. B, Dose-response effects. Nociceptin (0.1–10 µg/rat) or vehicle was injected icv, and rats were decapitated 10 min after the injection. Values are presented as mean ± SEM *, P < 0.05; **, P < 0.01 compared with control. Values are from the data of 6 rats at each point.

Exp 2: hyperosmolar and hypovolemic stimulation
After ip injection of HS, plasma Na⁺ increased from 139.7 ± 1.1 in control rats to 145.7 ± 0.4 mEq/liter (Table 1). Nociceptin (10 µg/rat) injected icv significantly suppressed the osmotically increased plasma AVP 10 min after the injection (1.16 ± 0.09 pg/ml vs. control, 1.82 ± 0.3 pg/ml; P < 0.05, Fig. 2). After ip injection of PEG, plasma TP increased from 5.85 ± 0.11 g/dl in control rats to 6.64 ± 0.08 g/dl, whereas plasma Na⁺ in the two groups was not significantly affected (Table 1). Nociceptin (10 µg/rat) injected icv significantly suppressed the hypovolemia-induced increase in plasma AVP (0.91 ± 0.16 pg/ml vs. control, 2.41 ± 0.26 pg/ml; P < 0.01, Fig. 2).

View larger version (49K): [in this window] [in a new window]   Figure 2. Effects of nociceptin (icv) on AVP release induced by hyperosmolality or hypovolemia. Rats were injected ip with hypertonic saline (HS: 600 mosml/kg; 2% BW) 30 min before decapitation. Nociceptin (10 µg/rat) or vehicle was injected icv, and rats were decapitated 10 min after the injection. Rats were injected ip with PEG (2% BW) 90 min before decapitation. Nociceptin (10 µg/rat) or vehicle was injected icv, and rats were decapitated 10 min after the injection. Control rats were injected with isotonic saline ip, and then isotonic saline was injected icv. Values are presented as mean ± SEM *, P < 0.05 compared with HS alone; **, P < 0.01 compared with PEG alone. Values are from the data of 6 rats in each group; Noci, nociceptin.

View larger version (40K): [in this window] [in a new window]   Figure 3. Effect of antagonist on icv nociceptin-induced inhibition on AVP release due to dehydration. All rats were deprived of water for 48 h. Nociceptin (10 µg/rat) or dynorphin A (10 µg/rat) was injected icv and rats were decapitated 10 min after the injection. Nor-BNI (1 µg/rat) or isotonic saline was injected icv 10 min before the icv injection of nociceptin or dynorphin A, Naloxone (2.5 mg/rat) was injected sc 35 min before the icv injection of nociceptin. Control rats were injected with isotonic saline icv. Values are presented as mean ± SEM **, P < 0.01 compared with control. #, P < 0.05 compared with vehicle group. Values are from the data of 6 rats per group; DYN, dynorphin A; BNI, nor-binaltorphimine; Noci, nociceptin; Nalo, naloxone.

View larger version (31K): [in this window] [in a new window]   Figure 4. Effect of icv injection of antinociceptin-As or NRS on plasma AVP suppressed by acute water loading. The oral water loading was performed 60 min before decapitation. Antinociceptin-As or NRS was injected icv at 15 min after water loading. Control rats for the oral water loading were decapitated without any treatment. Values are presented as mean ± SEM *, P < 0.05; **, P < 0.01 compared with control. #, P < 0.05 compared with NRS group. Values are from the data of 6 rats per group; NRS, normal rabbit serum; anti-noci-As, antinociceptin-antiserum.

	Discussion

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This inhibitory effect cannot be attributed to a decrease in the level of osmotic or hypovolemic stimulation, because plasma Na⁺ and TP were not affected by the icv injection of nociceptin. It is also unlikely that the change in blood pressure caused plasma AVP changes in the present experiments because icv nociceptin has been reported to produce a small fall in blood pressure (21, 26), which is well known to stimulate AVP secretion rather than inhibit AVP release.

The immunoneutralization of endogenous nociceptin by icv injection of antinociceptin-As significantly reversed the water loading-induced suppression of plasma AVP compared with NRS. The result indicates that the inhibition of AVP release under acute water loading is, at least in part, mediated by endogenous nociceptin.

Although the physiological role of nociceptin remains to be established, there are several reasons to hypothesize that it may be involved in cardiac and vascular control (26, 27, 28, 29, 30, 31). Previous studies have revealed that in conscious rats, a central infusion of nociceptin produced a profound increase in urine flow rate (21). Our data lend support to the idea that the reported diuretic actions of nociceptin, at least in part, could be attributable to inhibition of AVP release as a result of its inhibitory action.

Nociceptin has recently been shown to be involved in activation of the HPA axis. Repetto et al. reported that nociceptin produced a significant increase in plasma levels of glucocorticoid in rats (13). AVP is also a major stimulator of ACTH release from the anterior pituitary via V1b receptors (32, 33). On the other hand, there is a large body of evidence that glucocorticoid inhibits AVP release (34). Furthermore, our present studies showed that nociceptin suppresses the AVP release. These results suggest that there is a profound interaction between nociceptin and AVP in the regulation of the HPA axis.

There are a number of studies indicating that the opioid systems are involved in the regulation of AVP release (35, 36, 37, 38, 39). Most studies showed that opioids had an inhibitory effect on basal plasma AVP (36, 37, 38, 39), and increase in AVP in response to hyperosmolality or hypovolemia was significantly attenuated by opioid agonists (25). We showed that injection of naloxone, which crosses the blood-brain barrier (40) and has an affinity for all major opioid receptor subtypes (22), did not significantly reverse the inhibitory effect of nociceptin on AVP release. Moreover, those effects were not antagonized by the selective -opioid receptor antagonist, nor-BNI at concentrations sufficient to antagonize the inhibitory effect of dynorphin A. It has been shown that nociceptin does not interact with the µ-, -, or -opioid receptor (41), and that it has a specific receptor different from other opioid receptors (6, 7). Therefore, these results suggest that injected nociceptin in the present study suppressed the AVP release by interacting with its own receptor distinct from classical opioid receptors.

Although the exact sites of action of nociceptin injected icv were not obvious from the present study, it suppressed AVP secretion elevated by both hyperosmolar and hypovolemic stimuli, indicating that nociceptin has an effect on the efferent pathway for the secretion of AVP, which reflects the integrated inputs from osmoreceptor and baroreceptor systems. In addition, drugs injected icv can permeate readily into the hypothalamus yet not reach the posterior pituitary (42). These results suggest that endogenous nociceptin may thus have a functional role in the regulation of AVP secretion at the level of the hypothalamus.

It has been reported that there is no nociceptin peptide containing cells or mRNA in the SON and only a few in the magnocellular portion of the PVN, although SON and PVN have a considerable expression of the ORL1 receptor and nociceptin-positive fibers (14, 15). It is, therefore, possible that AVP neurons in SON and PVN may be innervated and modulated by nociceptin cells from other areas of the brain.

In conclusion, the results of the present study suggest that endogenous nociceptin is physiologically involved in regulation of the plasma AVP level through its inhibitory action.

Received June 2, 2000.

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