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Naloxone Disinhibits Magnocellular Responses to Osmotic and Volemic Stimuli in Chronically Hypoosmolar Rats

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Naloxone Disinhibits Magnocellular Responses to Osmotic and Volemic Stimuli in Chronically Hypoosmolar Rats
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  Journul OJ‘ Neuroen~ocrinolo~~v, 995, Vol 7, 57-62 ~ ~ ~~~~~ ~ ~ ~ Naloxone Disinhibits Magnocellular Responses to Osmotic and Volemic Stimuli in Chronically Hypoosmolar Rats Janos Dohanics and Joseph G. Verbalis Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15261, USA Abstract Normonatremic and chronically hyponatremic rats were pretreated with naloxone (5 mg/kg) or isotonic (1 50 mM) NaCI, then were given i.v. injections of 2 M NaCl (2 ml) or were hemorrhaged (20 ml/kg). Baseline and post-stimulus blood samples were withdrawn through indwelling jugular venous catheters. Baseline levels zyxwvutsr f plasma vasopressin (AVP) and oxytocin (OT) were similar in both normonatremic and hyponatremic rats and did not change after naloxone pretreatment. Increases in plasma AVP and OT levels in response to both hypertonic saline and hemorrhage were markedly blunted in the hyponatremic rats compared to the normonatremic rats. Naloxone pretreatment caused augmented AVP and OT secretion in response to hypertonic saline stimulation and hemorrhage in both the normonatremic and hyponatremic rats; the magnitude of the naloxone augmentations in the hyponatremic rats were sufficient to normalize the OT response to hypertonic saline and both the OT and AVP responses to hemorrhage. Our results therefore suggest that endogenous opioids are likely involved in the inhibition of stimulus-induced AVP and OT release that accompanies chronic hypoosmolality. Chronic hyponatremia is characterized by hypofunction of hypo- thalamic magnocellular vasopressin zyxwvut AVP) nd oxytocin (OT) neurons. Under resting conditions hyponatremic rats exhibit basal plasma levels of AVP and OT that are similar to those of normonatremic rats (1 ), but secretion of AVP and OT is markedly reduced in response to most stimuli, including i.v. injection or infusion of hypertonic saline ( 1-3), ip injection of cholecystokinin (CCK; l), S.C. injection of polyethylene glycol PEG; , 4) and hemorrhage (1). A further indication of the hypofunction of magnocellular neurons during chronic hyponatremia is the mark- edly decreased expression of both AVP and OT mRNA in the paraventricular PVN and supraoptic (SON) nuclei under these conditions 5). However, pituitary stores of AVP and OT remain intact even after weeks of sustained hyponatremia 5), and a few stimuli such as i.p. injection of CuSO, (6) and i.v. injection of 5-hydroxytryptophan (5-HTP; 7) induce AVP and OT secretory responses in hyponatremic rats that are equal to or greater than responses in normonatremic controls. These observations indicate that neurohypophyseal secretion can be stimulated under some conditions despite ongoing severe hypoosmolality, and suggested that alterations in stimulated AVP and OT responses could be utilized to study the central mechanisms responsible for osmotic inhibition of neurohypophyseal secretion. In normonatremic rats magnocellular neuronal function has been reported to be stimulated or inhibited by a number of different neurotransmitters (see 8 for review), many of which have also been identified in nerve terminals innervating hypothal- amic magnocellular nuclei (9). Prominent among these are opioids, which have been shown to inhibit AVP and OT responses to a wide variety of stimuli (10-14; however see also 15 which reports opioid stimulation of osmotically-induced AVP ecretion). No studies to date have investigated the potential effects of any of these neurotransmitters, including endogenous opioids, on magnocellular neuronal function under conditions of chronic physiological inhibition. In this study we evaluated the effects of hyperosmolality and hemorrhage on AVP and OT secretion in naloxone-pretreated hyponatremic rats and normonatremic con- trol animals, in order to determine whether the removal of any inhibitory influences of endogenous opioids by naloxone would allow restoration or improvement of the markedly impaired magnocellular secretory responses of these rats. Results Intravenous injection of 2ml of 2M NaCl caused rapid and marked increases in plasma “a+] levels of both normonatremic and hyponatremic rats, with peak increases of similar magnitude in both groups of animals. However, relative increases in plasma “a+] (A[Na+]) were significantly higher in hyponatremic rats than in normonatremic rats at sampling times after the peak occurred (Table I). There were no significant differences in the A[Na+] values between the control and naloxone-treated groups for both the normonatremic and hyponatremic rats. Naloxone treatment alone did not cause significant changes in basal plasma zyxw VP or OT concentrations in either the normona- tremic or the hyponatremic rats. However, peak plasma AVP concentrations in response to i.v. injection of 2 M NaCl in the naloxone-pretreated normonatremic and hyponatremic rats were larger by 36.3 pg/ml (158%) and by 9.7 pg/ml (165%), respect- Correspondence to: Janos Dohanics, E-I140 Biomedical Science Tower, University of Pittsburgh. Pittsburgh, PA 15261, USA.  58 Opioid effects in hypoosmolar rats TABLE . Effects of 2 M NaCl Injection (2 ml iv) on Plasma a+] Levels (mmol/l) in Normonatremic and Hwonatremic Rats. H yponatremic Delta *SEM a'] zyx   SEM ~ 130 1 40 1 80 zyx   79 14 70 59 43 15 30 1 00 *23 33 3 90 0 70 **I7 58 117 0 70 **I7 02 I 07 Normondtremic Plasma Delta a  I +SEM a+] 144 10 0 80 144 30 0 90 0 23 191 00 8 90 47 05 157 70 0 90 13 78 155 90 1 10 12 13 154 20 100 10 41 ~ zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDC EM 0.61 8.68 0.53 0.92 0.83 Plasma a+] Timc (min) 5.00 0.00 15.00 30.00 45.00 75.00 112.50 114.30 168.00 130.90 129.10 128.50 Delta a+] represents changes relative to the first plasma sample. *P<0.05. **P<0.01 compared to normonatremic rats. the plasma level curves revealed that significantly larger stimulated AVP secretion occurred in the normonatremic than in the hypona- tremic rats after both saline and naloxone pretreatment (Fig. lc). In contrast to the AVP results, stimulated OT secretion in the normonatremic rats was significantly larger than in the hypona- ively. than in their saline-pretreated counterparts (Fig. 1~). Following naloxone pretreatment, peak plasma OT responses to this stimulus were larger by 180.7pg/ml (103' 1) and by 231.4 pg/ml ( 1530' ,) n the normonatremic and the hyponatremic rats, respectively (Fig. 1~). tatistical analysis of the areas under zyxwv 4001 - - 3 1 0 401 - m 10 -30 -15 15 30 45 60 75 90 Time (mid OOr zyxwvutsrqponmlkjih   Time (min) t T 800 cl =t .I g 150L - T I U a, m t 50- E T ** n Saline Naloxone 0- Saline Naloxone FIG. . Effccts of 2 M NaCl injection (2 ml i.v.) on the time-course (panels zyxwvut , B) and total secretory responses (panels C. D) of plasma AVP (panels A, C and OT (panels R, D concentrations. Closed symbols: normonatremic rats: open symbols: hyponatremic rats: circles: I50 mM NaCl pretrcatment; triangles: naloxone pretreatment (panels zyxwvutsr   B). Solid columns: normonatremic rats; open columns: hyponatremic rats (panels C, D). Means +SEs are shown. *P<0.05, **P<0.01 coinpared to nomonatremic rats. tP<0.05. ftP<O.Ol compared to 150 mM NaCl pretreatment.  Opioid effects in hypoosmolar rats 59 Discussion zyxw   large number of studies have shown that opiate agonists inhibit AVP and OT release from the neurohypophysis (8), and that opiate antagonists such as naloxone enhance OT release, and to a more variable degree AVP release, evoked by various stimuli (8, 10, 13, 14, 16). Our results now extend these findings to chronically hyponatremic rats as well. The mechanism by which endogenous opioids inhibit magnocellular secretion remains unre- solved. Although naloxone is not specific for any of the known three major types of opiate receptors, it has at least 10 times greater affinity for zyxw   than for zyxw   receptors, and exhibits very little affinity for 6 receptors (18). In addition, the distribution of opioid receptor types along the hypothalmo-neurohypophyseal tract is uneven: all types of opiate receptors are present in the hypothal- amus (19), but only K receptors have been found in the posterior pituitary, where a large percentage of these receptors appears to be located on pituicytes (20). The p receptors found in the PVN and SON can potentially be activated by opioid innervations srcinating in the arcuate nucleus of the hypothalamus (21 ) and the brainstem (22). Together with the fact that naloxone readily crosses the blood-brain barrier, these observations suggest that a, m a, zyxwvutsrq   400 - ?? 00 zyxwv   > 300- 5 U (L1 U a, zyxwvutsrqponmlk m - 200- 00 I5 100- T - tj n n tremic rats following saline pretreatment, but after naloxone pretreatment the OT response of the hyponatremic rats was equivalent to that of the normonatremic rats (Fig. 1~). Peak plasma AVP concentrations in response to two sequential hemorrhages in the naloxone-pretreated normonatremic and hyponatremic rats were larger by 79.9 pg/ml (52 ) and by 189.3 pg/ml (328 ), respectively, than in their saline-pretreated counterparts (Fig. 2A). Following naloxone pretreatment, peak plasma OT responses to this stimulus were larger by 59.5 pg/ml (293 ) and by 236.4 pg/ml (871 ) in the normonatremic and in the hyponatremic rats, respectively (Fig. 26). Statistical analysis of the areas under the plasma level curves revealed that stimulated AVP secretion in the normonatremic rats was significantly larger than in the hyponatremic rats following saline pretreatment, but after naloxone pretreatment the AVP response of the hypona- tremic rats was equivalent to that of the normonatremic rats (Fig. 2c . Similarly, stimulated OT secretion in the normona- tremic rats was significantly larger than in the hyponatremic rats following saline pretreatment, but after naloxone pretreatment the AVP response of the hyponatremic rats was equivalent to that of the normonatremic rats (Fig. 2D). T a loot --- s n J' 1 I, , I YI - -20 -10 10 20 30 40 50 60 70 Time (min) 7OOr c 600 500 tt TT J -20 -10 0 10 20 30 40 50 60 70 Time (min) tt T - Saline Naloxone Saline Naloxone FIG. 2. Effects of two consecutive hemorrhages (10 ml/kg each) on the time-course (panels A, B) and total secretory responses (panel c AVP (panels A, c and OT (panels B, D) concentrations. Closed symbols: normonatremic rats; open symbols: hyponatrernic rats; circles: pretreatment; triangles: naloxone pretreatment (panels A, B). Solid columns: normonatremic rats; open columns: hyponatremic rats Means zyxwvutsrq   Es are shown. *P<0.05, **PiO.OI compared to normonatrernic rats, ttP<O.OI compared to 150 mM NaCl pretreatment. _- D) of plasma 50 mM NaCl panels c, D).  60 Opioid effects in hypoosmolar rats the amplifying effect of systemic naloxone administration on hypertonic saline- and hemorrhage-induced AVP and OT secre- tion observed in this study may be mediated by zyxwvuts u receptors located at the level of the magnocellular cell bodies in the PVN and SON. or further upstream on neuronal pathways conveying these stimuli, rather than at the level of the neurohypophysis. Against this possibility are previous electrophysiological studies showing that naloxone administration does not alter the electrical activity of magnocellular neurons in the SON ( 17). Although this argues in favor of an action of naloxone at neural lobe zyxwvu   opioid receptors to potentiate AVP and OT secretion in normonatremic rats, analogous electrophysiological studies in hyponatremic rats will be necessary to evaluate this possibility. The naloxone responses of the hemorrhaged rats were particu- larly dramatic. zyxwvutsrqp s reported previously, hyponatremic rats exhibit significantly smaller AVP and OT secretory responses compared to normonatremic controls following graded hemorrhages ( 1 ). However, after naloxone pretreatment both the AVP and the OT responses in the hyponatremic rats were indistinguishable from the augmented plasma levels of the naloxone-treated normona- tremic controls. These observations strongly suggest that during chronic hyponatremia a significant part of the impaired AVP and OT responses to hypovolemic stimuli may be due to an increase in the activity of inhibitory opioid neurons that impinge on pathways carrying these stimuli to AVP and OT magnocellular neurons. Because of the systemic nature of the naloxone treatment in these studies, we are unable to localize the site(s) at which naloxone may be acting to inhibit hypovolemia-stimulated path- ways. Many brain areas that receive projections from barorecep- tive fields of the NTS also contain opioid peptides and receptors, including the ventrolateral medulla, subforiiical organ. and anterior hypothalamus (33-26). However, the opioid neurons that participate in the osmotic inhibition of neurohypophyseal secretion must either receive osmosensitive inputs, or possess intrinsic osmosensitive properties, in order to be capable of increasing the level of endogenous opioid tone during hypoosmo- lar conditions. For this reason, the possibility of opioid projections from the anterior hypothalamus to the SON and PVN is particu- larly noteworthy, since this is an area that is known to possess osmoreceptive inputs (27) as well as projections from brainstem baroreceptive inputs (35, 28, 29), and thus is well situated to represent a site capable of integrating osmotic and cardiovascular afferent information. Although OT responses to hyperosmotic stimuli in hypona- tremic rats approximated those in normonatremic rats following naloxone treatment, the AVP responses in hyponatremic rats remained significantly smaller than those in normonatremic rats. Thus, while elimination of opiate inhibition did increase the plasma AVP responses significantly in the hyponatremic rats, naloxone treatment did not fully restore AVP secretory function to the levels found in the naloxone-pretreated normonatremic controls. These observations suggest that while the inhibitory effect of endogenous opioids are sufficient to account for the blunted hemorrhage-induced AVP and OT responses and the hypertonic saline-stimulated OT response, the more limited res- toration of the hypertonic saline-induced AVP response following naloxone treatment suggests the presence of additional naloxone- insensitive inhibitory mechanisms that impair osmotically stimu- lated AVP secretion. One possibility for this residual inhibition would be an effect of dDAVP itself to inhibit AVP secretion. Such an effect has been reported in studies employing large doses (35 ng) of dDAVP (30). but previous studies from this laboratory have shown normal AVP secretion in response to hyperosmolality in dDAVP-infused rats once normonatremic levels of plasma “a+] are achieved (1, 2). It therefore seems more likely that additional inhibitory central pathways are responsible for mediat- ing inhibition of AVP secretion. One possibility for such additional inhibitory inputs are GABAergic pathways. GABA projections from the diagonal band of Broca appear to be responsible for the inhibition of AVP secretion produced by hypertension (31 . and more recently the possibility of an inhibitory GABAergic innervation of the SON and PVN srcinating in the anterior hypothalamus has been described (33 . Elucidating the physiological roles of specific opioid pathways in the control of AVP and OT secretion is likely to be challenging. An example of this is provided by recent studies which demon- strated the involvement of opiate receptors in the lateral para- brachial nucleus for full expression of the effects of hypovolemia, but not hypotension, on AVP secretion in rats (33). This therefore represents an area where opioids appear to be necessary for the stimulation of AVP secretion rather than inhibition of AVP and OT secretion. Interestingly, diprenorphine, a non-specific opioid receptor antagonist, but not naloxone, caused an inhibition of hypovolemia-stimulated AVP secretion ( 33 ). indicating that sep- arate and distinct opioid systems in different parts of the brain exert specific, and sometimes antagonistic, effects on AVP and OT secretion. Similar types of effects at different opioid receptors might also explain the discrepancy between our results and others ( 10-14) versus those reported by Cheng et al. ( lS), who found an inhibition of osmotically-induced AVP secretion in rats treated both acutely and chronically with naloxone. The smaller dose of naloxone used in that study (1 nig/kg) may have resulted in a selective effect at specific sites and/or types of opioid receptors to inhibit AVP secretion, an effect that may have been masked by a greater stimulatory action at a different site and/or receptor type of the larger dose of naloxone used in our study. Despite the inherent complexity of central opioid effects on neurohypophyseal secretion, the present studies add further sup- port to the likelihood that an active osmotic inhibition may be present under conditions of chronic hypoosmolality ( 34 ), and indicate that endogenous opioids likely play a significant role in mediating these effects. Methods Male Sprague-Dawley rats ( 250-300 g) were housed individually in wire- mesh cages in a temperature-controlled room (21-23 C) with lights on from 7.00 to 19.00. Hyponatremia was induced as described previously z 35). Briefly, rats were fed with 40 ml a day (70 kcal/day) of a nutritionally balanced liquid diet ( AIN-76, Bioserv, Frenchtown, NJ, USA , which was presented daily each morning until the day of experimentation. After 2 days on liquid diet. osmotic minipumps (Alzet model 1007, Alza. Palo, Alto, CA. USA containing 1-deamino-[ 8-D-arginine]-vasopressin (dDAVP, Rorer Pharmaceuticals, Fort Washington, PA, USA) were implanted subcutaneously using methoxyflurane ( Metofane, Pitman- Moore, Inc., Washington Crossing, NJ, USA) anesthesia to deliver the dDAVP at a rate of 5 ng/h. dDAVP was chosen as the antidiuretic agent since it has a very low affinity for pituitary AVP receptors ( 36). On the day of osmotic minipump implantation the rats were given a more diluted preparation of the liquid diet (70 kcal in 60 ml ), but thereafter resumed the more concentrated formula (70 kcal in 40 ml). Control rats received the same diet but were not implanted with dDAVP-containing minipumps. Eight to 10 days after the dDAVP infusion had begun, silastic catheters  were implanted into the right jugular vein using methoxyflurane anes- thesia. Experiments were carried out on days 10-12 of the dDAVP infusion. At that time plasma "af] in the dDAVP-infused rats was 112k I zyxwvutsrqponmlkj S 142 1 mmol/l in controls maintained on the same volumcs of the liquid diet (P<O.OI). The normonatremic and hyponatremic rats were subjected to either i.v. injection of 2 M NaCl (2 ml) or two sequential hemorrhages (10 ml/kg each at 5 min intervals). Fifteen min prior to administration of these stimuli a baseline blood sample zyxwvutsrqp   zyxwvutsrq   ml) was withdrawn, followed immedi- ately by i.v. administration of 0.9' 4 NaCl or zyxwvutsrq   nig/kg naloxone (in 1 ml of 150 mM NaCl). This dose of naloxone was chosen based on previous studies which demonstrated the efficacy of this dose to potentiate OT secretion in response to parturition (13) and hyperosmolality (14). The i.v. route of administration was chosen to avoid any effects of stress as a result of pain associated i.p. or S.C. injections. Another blood sample was withdrawn just prior to administration of either stimulus, and additional blood samples were withdrawn after the hypertonic saline administration or hemorrhages were completed. Blood samples were drawn into heparin- ized borosilicate glass tubes which were immediately placed on ice. For all studies blood samples were centrifuged in a refrigerated centrifuge 3000~) ithin 30 min: loop1 of the plasma was used for immediate measurement of "a+] and the remainder was stored at -20'C for radioimmunoassay of AVP and OT. Radioimmunoassays of plasma AVP and OT were performed in our laboratories using methods described previously (6). Since this assay uses an antibodies that recognizes the -COOH terminus of AVP, it does not significantly cross-react with dDAVP present in plasma samples I, 2). zyxwvut ll values are presented as means + SEs. Statistical analysis was performed on logarithmic transform of data because of inhomogeneity of variances. Significance was assessed by ANOVA followed by Dunn's test for multiple comparisons (37). Acknowledgements Thc authors wish to thank Darina Sipula for technical assistance with the performance of the radioimniunoassays. These studies were supported in part by funds from NIH grants DK 02014 (J.D.) and DK38094 (J.G.V.). Parts of this work were presented in abstract form at the 74th Annual Meeting of the Endocrine Society. San Antonio, TX. USA, 1992. Accepted 19 September 1994 References I. Verbalis JG. Dohanics J. ( 1991). Vasopressin and oxytocin secretion in chronically hypoosmolar rats. Amer J Physiol. 261: RI 028-R 1038. 2. Verbalis JG. Baldwin EF, Robinson AG. (1986). 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