FABAD J. Pharm. Sci., 28, 27-37, 2003

SCIENTIFIC REVIEWS Control of Renal Excretion of Water and Sodium

Sena F. SEZEN*°

Opioid Control of Renal Excretion of Water and Sodium Su ve Sodyumun Böbreklerden At›l›m›n›n Opioid Kontrolü Summary : The kidneys act to regulate total body water and Özet : Vücudun su ve sodyum dengesinin böbrekler taraf›ndan sodium via numerous neural and humoral mechanisms, inclu- düzenlenmesinde pek çok nöronal ve hormonal faktörler (renal ding pathways that involve the renal sympathetic nerves, anti- sempatik sinirler, antidüretik hormon, atriyal natriüretik faktör, diuretic hormone, atrial natriuretic factor, and the renin-angi- renin-anjiyotensin-aldosteron sistemi gibi) rol oynarlar. Bunla- otensin-aldosterone system. In addition to these pathways, evi- ra ilave olarak, opioid sistemlerin de renal fonksiyonun regü- dence indicates that systems participate in regu- lasyonunda rol oynad›¤› flu bulgulara dayan›larak önerilmek- lation of the renal excretory function by modulating neural tedir: a). do¤al veya sentetik opioid agonistlerin direkt santral, and/or humoral pathways within the kidneys, periphery or periferik veya intrarenal olarak uygulanmalar›n›n renal su ve central nervous system. Briefly, this premise stems from the fol- sodyum at›m›nda de¤iflikli¤e neden olmas›, b). endojen santral lowing findings: a) central, peripheral, and intrarenal administ- opioid mekanizmalar›n farkl› stress modellerinde oluflan renal ration of native and synthetic opioid produces chan- fonksiyon de¤iflikliklerinde rol oynamas›, c). vücudun s›v› den- ges in the renal excretion of water and sodium, b) endogenous gesinin bozuldu¤u patolojilerde gözlenen renal at›m bozukluk- central opioid mechanisms participate in the cardiovascular lar›nda endojen opioid sistem fonksiyonu de¤iflikliklerin rol oy- and renal responses produced by psychoemotional (air jet namas›. stress) and dietary (sodium deficiency) stress, and c) endogeno- Opiodlerin etkileri mu, kappa ve delta olarak adland›r›lan bafl- us opioid systems contribute to the deranged renal excretory l›ca 3 tip opioid reseptörü arac›l›¤› ile oluflur. Opioidlerin renal responses observed in the pathology of cirrhosis with ascites. fonksiyon regulasyonuna etkilerinin incelendi¤i pek çok çal›fl- The actions of are mediated by 3 types of opioid receptors mada, selektif opioid reseptör agonistlerinin uygulamas›n›n,et- named mu, kappa and delta. Administration of selective opioid kiledi¤i reseptöre ba¤l› olarak diürez/antidiürez ve natri- agonists can produce diuresis/antidiuresis and natriuresis/antinat- ürez/antinatriürez oluflturdu¤u gösterilmifltir. Opioid sistemlerin riuresis depending on the type of opioid receptors activated. To böbrek fonksiyonunu nas›l etkiledi¤inin anlafl›lmas›nda her bir completely understand how opioid systems influence kidney func- opioid reseptör alttipinin renal su ve sodyum at›l›m›na etkileri- tion, it is important to understand how each opioid system acts in- nin anlafl›lmas› önem tafl›maktadir. Bu kapsamda, mu, kappa, dividually or in concert to alter renal function. In that regard, con- delta ve yeni tan›mlanan ORL-1 reseptörlerinin renal fonksiyo- siderable research has been performed to elucidate the role of mu, na etkilerini tan›mlamaya yönelik pek çok çal›flma yap›lm›flt›r. kappa, delta and the recently discovered -like Bu makalenin amac›, çeflitli opioidlerin renal su ve sodyum at›- 1(ORL-1) receptors in renal excretory function. m›na etkileri ve etki mekanizmalar›n›n anlafl›lmas›na yönelik The purpose of this article is to provide a brief review of the çal›flmalar›n de¤erlendirilmesidir. particular renal responses produced by opioids and the mecha- Anahtar kelimeler: opioid, renal, diürez, natriürez, ADH, renal nism(s) by which these compounds affect renal function. sempatik sinirler Key Words: opioids, kidney, diuresis, natriuresis, ADH, renal sympathetic nerves Received : 7.11.2002 Revised : 9.6.2003 Accepted : 10.6.2003

1. INTRODUCTION known to humans. It has been used for thousands of years for relieving pain and diarrhea and also for its , the dried exudate of the juice of the poppy mood changing effects. In the beginning of the 19th , is one of the oldest drugs century, was isolated from opium and

* Department of Pharmacology, School of Pharmacy, Marmara University, T›bbiye Cad. No: 49 Haydarpafla, 81010 Istanbul, Turkey ° Corresponding author

27 Sezen shown to be the principle alkaloid responsible for dium15,16,17. In addition, the kidneys play a pivotal this extract's medicinal and non-medicinal effects. role in the regulation of arterial blood pressure by Despite morphine's long history, the breakthrough regulating body fluid volume and sodium con- in understanding the actions of morphine and other tent17,18. As a consequence of the kidneys' homeos- opioid compounds (e.g. ) did not begin until tatic role, the tissues and cells of the body are able to the identification of opioid receptors and endogeno- carry out their normal functions in a relatively cons- us opioid peptides1,2,3,4. With the development of tant environment. selective opioid agonists and antagonists, it has be- come clear that each subtype of opioid receptor is The kidneys act to regulate total body water and so- differentially distributed in the central nervous sys- dium via numerous neural and humoral mecha- tem (CNS) and periphery5,6, and exerts unique nisms, including pathways that involve the renal pharmacological properties7. The opioid systems sympathetic nerves, antidiuretic hormone (ADH), have been implicated in mediating a broad range of atrial natriuretic factor (ANF), and the renin-angi- behavioral and functional responses such as reinfor- otensin-aldosterone system 16,19-21. In addition to cement and reward, neuroendocrine modulation, these pathways, evidence indicates that opioid pep- neurotransmitter release, and the regulation of gast- tide systems may participate in regulating the renal 8,9 rointestinal, cardiovascular and immune functions8. excretory function . Briefly, this premise stems from the following findings: a) central, peripheral, In addition to the physiological processes menti- and intrarenal administration of native and synthe- oned above, opioids participate in the regulation of tic opioid agonists produces changes in the renal 9 renal function9. Under different conditions, exoge- excretion of water and sodium , b) endogenous nous and endogenous opioids have been shown to central opioid mechanisms participate in the cardi- produce marked changes in the renal excretion of ovascular and renal responses produced by psycho- emotional (air jet stress) and dietary (sodium defici- water and sodium via multiple neural and hormo- ency) stress22,23, and c) endogenous opioid systems nal mechanisms9-12. Opioids evoke changes in uri- contribute to the deranged renal excretory responses ne output and urinary sodium excretion by modula- observed in the pathology of cirrhosis with as- ting neural and/or humoral pathways within the cites24-26. The particular renal responses produced kidneys, periphery or central nervous system13,14. by opioids and the mechanism(s) by which these To completely understand how opioid systems inf- compounds affect renal function will be discussed luence kidney function, it is important to unders- next. tand how each opioid system acts individually or in concert to alter renal function. In that regard, consi- 2.1 EFFECTS OF MU OPIOID SYSTEMS ON RE- derable research has been performed to elucidate NAL EXCRETION OF WATER AND SODIUM the role of mu, kappa, delta and recently discovered opioid receptor-like 1 (ORL-1) receptors in renal exc- Morphine, a prototype mu opioid , produces retory function. The purpose of this article is to pro- an antidiuretic effect in humans and other species vide a brief review of the effects and mechanism of 27,28. In anesthetized dogs, morphine was suggested action of various opioids on the regulation of renal to decrease urine output by stimulating the secreti- excretion of water and sodium. on of ADH29. However, under different experimen- 2. EFFECTS OF OPIOID SYSTEMS ON RENAL tal conditions, the administration of a mu opioid EXCRETORY FUNCTION agonist has been shown to produce an increase in urine output. For instance, peripheral or central ad- One of the important functions of the kidneys is to ministration of mu opioid agonists (e.g. morphine, maintain body fluid and electrolyte balance despite levarphanol and ) produce antidiuresis wide variations in the daily intake of water and so- in rats hydrated with an oral water-load28,30-32. In

28 FABAD J. Pharm. Sci., 28, 27-37, 2003 contrast, in conscious rats that are normally hydra- studied, factors such as the method of urine collecti- ted, peripheral or central administration of a mu on (i.e. bladder cannulation or spontaneous voiding) opioid agonist (e.g. morphine, ) produ- and variations in experimental protocols (duration ces a marked diuretic response11,14,30,33,34. Despite of urine sampling) may contribute to the variability the variable effects on urine output, central or perip- of mu opioids on urine output. In regard to differen- heral administration of mu opioid agonists consis- ces in experimental methods, it should be noted that morphine inhibits the micturition reflex and can ca- tently decrease urinary sodium excretion (i.e. pro- use urinary retention27 (i.e. antidiuresis). Therefore, duce antinatriuresis)23,33,35. in certain studies in which urine samples were col- lected via a bladder cannula, this inhibitory effect of Several mechanisms have been proposed to explain morphine on bladder contractility may have been the variable effects that morphine and other mu prevented, and a mu-opioid-induced diuretic res- opioid agonists have on the renal excretion of water. ponse revealed. Marchand30 suggested that the differences in morp- hine's effect on urine output (i.e. diuresis or antidi- A number of investigations have reported that mu uresis) depend on the prior hydration status of the opioid agonists can increase the plasma levels of animal studied. Thus, morphine and other mu opi- ANF40-43 . Enhanced release of ANF has been sug- oid agonists produce antidiuresis in water-loaded gested to contribute to the diuretic effects of morp- animals via stimulating ADH release28,30,36. On the hine and other mu opioid agonists11,14 . In consci- other hand, in normally hydrated or water- ous, normally hydrated rats, i.c.v. administration of restricted rats, mu opioid agonists are suggested to morphine produced a significant increase in urine produce diuresis via suppressing ADH secreti- output which was accompanied by an increase in on34,37,38. plasma ANF. These responses occurred without sig- nificant changes in systemic hemodynamics11 . In Despite these findings, the role of ADH in mediating addition, in the same study, pretreatment of animals the renal responses to mu opioids has been questi- with ANF-antibody prevented the morphine-indu- oned. In this regard, other research investigations ced diuresis, verifying the role of ANF in this renal have shown that: 1) morphine produced diuresis in response. In other studies, these investigators estab- Brattleboro rats, a genetic strain of rodents that lack lished that mu opioids act peripherally to promote ADH39 and 2) administration of morphine to rats the release of ANF. This premise was supported by does not produce the same pattern of change in uri- the finding that i.v. administration of TAPP, (a high- nary electrolyte excretion as does administration of ly selective mu-opioid receptor agonist that lacks the ADH31,35 . Therefore, mechanisms other than stimu- ability to cross the blood-brain barrier), also produ- lation of ADH release have been suggested to cont- ced a marked increase in plasma ANF and urine ribute to the antidiuretic effects of mu opioid ago- output in conscious rats14. nists such as change in renal blood flow (RBF) and/or glomerular filtration rate (GFR). A study by Despite the variable effects of mu opioids on the re- Kapusta and Dzialowski12 showed that intracereb- nal excretion of water, morphine and other mu opi- roventricular (i.c.v.) administration of dermorphin, oid agonists consistently produce a decrease in uri- a selective mu opioid receptor agonist, produced a nary sodium excretion (i.e. antinatriuresis). Initially, diuretic and antinatriuretic effect in conscious rats. it was proposed that the decrease in urinary elect- The diuretic, but not the antinatriuretic, response rolyte excretion resulted from a reduction in blood was abolished by intravenous (i.v.) infusion of pressure and GFR28,31. However, morphine and ot- ADH, suggesting that the diuretic effect of central her mu opioid agonists have been shown to produ- mu opioids involved changes in circulating levels of ce a marked decrease in urinary sodium excretion ADH. In addition to the water balance of the animal without changing GFR or systemic hemodyna-

29 Sezen mics10,33. Continued research in this area has de- hydration status of the animal has been suggested to monstrated that mu opioid agonists produce a dec- play an important role in the renal excretory respon- rease in urinary sodium excretion via complex mec- ses produced by mu opioids30. Similarly, Leander et hanisms that involve central, adrenal and direct re- al.53 conducted experiments to examine how diffe- nal actions13,34 . It has been suggested that mu opi- rent hydration conditions may effect the ability of oids may cause antinatriuresis by a pathway that in- kappa opioid agonists to affect urine output. These volves the renal sympathetic nerves. Renal sympat- studies reported that all kappa opioid receptor ago- hetic nerves play an important role as a neural link nists studied (, EKC, U-50,488H) pro- between the CNS and the kidney44. All functional duced a diuretic response under different hydration units of the kidneys (tubular and vascular) are den- conditions (water loading, euhydration, dehydrati- sely innervated with renal sympathetic nerves. Gra- on). Thus, increased urine output has been sugges- ded electrical stimulation of the renal nerves causes ted as a simple in vivo test for studying the actions frequency dependent increases in renin secretion, of compounds on kappa opioid receptors47,48. The renal tubular sodium and water reabsorption, and diuretic response produced after central or periphe- decreases in RBF and GFR, thus causing a marked ral administration of the kappa opioid receptor ago- decrease in urinary sodium and water excretion. nist appears to involve an action of the drug to inhi- The role of the renal nerves in producing mu-opioid bit the release of ADH from the pituitary. In consci- induced antinatriuresis has been studied by Kapus- ous rats, subcutaneous (s.c.) injection of EKC, a kap- ta et al.34. In their studies, central administration of pa opioid receptor agonist, produced a dose-depen- dermorphin, a highly selective mu opioid receptor dent increase in urine output54. In these studies, the agonist, produced a marked diuresis and a concur- plasma levels of ADH were significantly reduced at rent reduction in urinary sodium excretion and inc- a time when urine flow was increased. It has been reased renal sympathetic nerve activity over the co- shown that kappa opioid agonists that cross the blo- urse of the antinatriuresis. This latter finding sug- od-brain barrier are potent diuretics. In contrast, gests that central dermorphin may have mediated kappa opioid analogs with limited ability to penet- an antinatriuretic response by increasing sympathe- rate the brain have little efficacy as diuretics51. It has tic outflow to the kidneys. However, additional been suggested that kappa agonists produce diure- mechanisms other than the renal nerves also appear sis by a mechanism that involves central kappa opi- to participate in mediating mu-opioid induced anti- oid receptors protected by the blood-brain barrier natriuresis since bilateral renal denervation did not (i.e. sites other than those accessible from the perip- completely abolish this renal response. In regard to heral circulation)51. Administration of a kappa ago- other mechanisms, it has been speculated that alte- nist (e.g. EKC), or a water load (e.g. gavage) to an rations in the secretion of hormonal substances from animal produces diuresis. However, while each ma- the pituitary or adrenal gland might be involved in nipulation reduces plasma ADH to equivalent le- mediating central mu opioid-induced changes in vels, EKC produces a greater magnitude increase in urinary sodium excretion34. urine output54. It has been suggested that a portion of the diuresis may be mediated by the actions of 2.1 EFFECTS OF KAPPA OPIOID SYSTEMS ON RE- kappa opioids to inhibit the effects of ADH in the NAL EXCRETION OF WATER AND SODIUM kidneys. Slizgi and Ludens54 demonstrated that EKC produced a dose-dependent inhibition of va- It is well established that central and/or peripheral sopressin-stimulated water flow across the toad administration of various kappa opioid receptor bladder, a model of the late renal distal tubule and agonists (e.g. U-50,488H, [U-62,066E], collecting duct. This suggests that the diuretic acti- ethylketocyclazocine [EKC], bremazocine) produces vity of EKC may have resulted from blockade of the characteristic diuresis in a number of species inclu- renal actions of ADH. This mechanism appears to be ding rats, mice, dogs, and humans45-52. The prior possible since kappa opioid receptors have been

30 FABAD J. Pharm. Sci., 28, 27-37, 2003 identified in rat kidneys54. Despite these findings, Administration of kappa opioids decreases the uri- however, kappa opioids have not been shown to al- nary excretion of sodium and urine osmolality. In ter ADH-mediated water transport in the mammali- conscious rats, i.c.v. administration of U-50,488H an collecting duct. Important to this latter observati- (1µg total), a selective kappa opioid agonist, incre- on, it should be noted that kappa opioids, with limi- ased urine flow rate and decreased urinary sodium ted ability to cross the blood-brain barrier, are only excretion. In these studies, U-50,488H also produced weak diuretics. Thus, inhibition of ADH secretion an increase in efferent renal sympathetic nerve acti- by the central action of kappa opioids is thought to vity during the duration of the antinatriuretic res- play a predominant role in mediating kappa-opioid ponse52 . Prior bilateral renal denervation prevented induced diuresis. By either pathway, attenuation of the decrease in urinary sodium excretion produced the actions of ADH at the level of kidneys or CNS re- by i.c.v. U-50,488H. Therefore, it was concluded that sults in enhanced excretion of water and diuresis. central kappa opioids produce antinatriuresis via an An action of kappa opioids to suppress the renal ac- increase in sympathetic outflow to the kidneys. In tion or CNS release of ADH is supported by studies addition, it should be noted that the antinatriuresis which have observed that the diuretic response pro- produced by peripheral administration of U- duced by these compounds is abolished by admi- 50,488H (and other kappa opioid agonists) may in- nistration of the vasopressin analogue, desmopres- volve simultaneous activation of both renal nerve- sin55. Moreover, kappa agonist administration does dependent (central) and -independent pathways. not elicit a diuresis in Brattleboro rats that are gene- This is suggested since the antinatriuretic response tically deficient in ADH56,57 . produced by i.v. infusion of kappa opioids was not abolished by prior bilateral renal denervation63. It is Despite inhibiting the secretion and/or renal action possible that the renal nerve-independent pathways of ADH, kappa opioids are suggested to evoke di- involve kappa opioid-induced changes in the secre- tion of other factors such as renin, aldosterone or ca- uresis by a pathway independent of this hormone. techolamines. Although opioids have been reported For instance, studies by Rimoy et al.58, and Reece et to affect the plasma levels of these substances64,65, al.59 demonstrated that the selective kappa opioid it remains to be established whether these alterati- agonists, spiradoline (U-62066) and CI-977, incre- ons trigger the subsequent changes in renal functi- ased urine output in human subjects without chan- on. ging plasma ADH. Similarly, the kappa opioid ago- nist, bremazocine, increased water excretion in rats 2.3 EFFECTS OF DELTA OPIOID SYSTEMS ON RE- without altering plasma ADH levels48,55 . Related to NAL EXCRETION OF WATER AND SODIUM these findings, it has been suggested that the diure- tic effect of kappa opioids might be mediated by a The role of delta opioid systems in the regulation of substance released from the adrenal glands. This renal function is less well characterized compared hypothesis stems from the findings that, in rats, bi- with mu or kappa opioids. However, several lines of lateral adrenalectomy prevents the kappa opioid-in- evidence suggest that delta opioid systems may, in duced diuresis57,60,61. In related studies, Wang et fact, have important influences on the renal hand- ling of water and sodium. First, delta opioid recep- al.62 proposed that kappa agonists increase the rele- tors are also widely distributed in CNS regions in- ase of epinephrine from the adrenal gland, and this volved in the regulation of cardiovascular function catecholamine stimulates alpha-2 receptors in the and fluid and electrolyte balance5,66-68, and are also kidneys to produce diuresis. This premise was ba- located in peripheral tissues such as the kidneys and sed on the observation that the kappa agonist-indu- the adrenal glands6 . Indirect evidence to support ced diuretic response was abolished by pretreat- this possibility comes from the observation that ment of animals with the alpha-2 receptor antago- central/ peripheral administration of methionine- nist, yohimbine.

31 Sezen and leucine- evoke changes in renal exc- ment with , the selective delta opioid re- retory function69-72. Since both methionine- and le- ceptor antagonist, indicates that in fact these respon- ucine- enkephalin have a high affinity for delta opi- ses were mediated by central delta opioid receptors. oid receptors, it is possible that these endogenous However, the difference in urinary sodium excreti- opioids mediate their renal responses via a delta on in response to peripheral or central administrati- opioid receptor pathway. The first direct evidence on of the selective delta agonists should be further for the role of delta opioids on renal excretory func- investigated. tion comes from our work in which peripheral ad- ministration of BW373U68 (BW) caused diuresis It can be concluded that, when activated, opioid sys- and natriuresis in rats73 . BW is a non-peptide that tems (mu, kappa, and delta) act collectively to incre- has been demonstrated to be a selective delta opioid ase urine output. Interestingly, selective mu and receptor agonist in various in vivo and in vitro stu- kappa opioid agonists produced a significant decre- dies74,75. In conscious rats, i.v. infusion of BW mar- ase in urinary sodium excretion, whereas, activation kedly increased urine flow rate and urinary sodium of delta opioid receptors either did not alter the uri- excretion without altering systemic or renal he- nary sodium excretion or produced a change in an modynamics. In these studies, the peripheral admi- opposite direction (i.e. natriuresis). It appears that nistration of SNC-80, a non-peptide delta opioid re- opioid systems can differentially alter the renal exc- ceptor agonist, also produced a profound diuretic retion of sodium upon activation. and natriuretic responses73. A major finding of this study is the observation that the renal excretory res- 2.4 EFFECTS OF /ORPHANIN FQ ponses produced by BW and SNC were dependent ON RENAL EXCRETION OF WATER AND SODI- on intact renal nerves. The diuresis and natriuresis UM produced by i.v. infusion of BW were abolished in rats having undergone chronic bilateral renal dener- Nociceptin/ Orphanin FQ (N/OFQ) is an endoge- vation, indicating that renal responses produced by nous opioid-like peptide that has been isolated from peripheral administration of the delta opioid recep- brain tissue77,78 and shown to be the endogenous li- tor agonist are mediated via a renal nerve-depen- gand of the ORL-1 (opioid receptor-like 1) receptor. dent pathway. Although not tested in these studies, ORL-1, in fact, is a new receptor protein that has be- BW may cause diuretic and natriuretic response by en identified in mice CNS and human and murine altering (i.e. decreasing) sympathetic outflow to the cDNAs have also been characterized79,80. N/OFQ, kidneys, the release of the neurotransmitter from the its precursor prepro-N/OFQ and ORL-1 are distri- nerve terminals, or the postsynaptic renal tubular buted throughout the CNS regions known to be in- (or vascular) actions of norepinephrine. Further stu- volved in the regulation of autonomic and cardi- dies are required to explore the role of these path- ovascular function, fluid and electrolyte balance ways in mediating renal responses produced by BW such as the paraventricular and supraoptic nucleus and other delta opioid ligands. of the hypothalamus, the central amygdala, the nuc- leus of the solitary tract, and in pre-vertebral and pa- We have also investigated the role of central delta ra-vertebral ganglia79-81. In addition to the presence opioid systems on renal excretory function. In these of ORL-1 transcripts in CNS, ORL-1 receptors are al- studies, the selective delta opioid agonists SNC-80 so located in peripheral organs such as the spleen, and DPDPE were administered directly to the CNS intestine, vas deferens and kidneys82,83. via an i.c.v. cannula and our preliminary results in- dicate that central administration of the either drug N/OFQ was shown to be involved in nociception, produced a profound increase in urine output wit- producing nociceptive or antinociceptive actions de- hout altering urinary sodium excretion in conscious pending on the experimental conditions. Subsequ- rats76. The inhibition of the responses by pretreat- ent research demonstrated that, similar to classical

32 FABAD J. Pharm. Sci., 28, 27-37, 2003 opioid systems, N/OFQ evokes marked changes in fects of this peptide because: a). changes in efferent other biological systems including cardiovascular renal nerve activity should produce reciprocal alte- and renal functions84. Initially, we have demonstra- rations in urinary sodium excretion, thus, such dec- ted that intravenous infusion of N/OFQ produced rease in renal nerve activity is not in accord with a a profound increase in urine flow rate and a decre- mechanism of antinatriuretic action, b). in animals ase in urinary sodium excretion in conscious Spra- that have undergone chronic bilateral renal dener- gue-Dawley rats85. In further studies, central admi- vation, renal responses to the central administration nistration of N/OFQ into conscious animals produ- of the peptide were not altered85. Therefore, these ced a concurrent diuresis and antinatriuresis85. Pre- results indicate that despite the decrease in renal vious investigations on opioid systems demonstra- nerve activity, renal sympathetic nerves are not in- ted that ORL-1 receptor and its endogenous ligand, volved in antinatriuretic effects of N/OFQ. N/OFQ have a sequence homology most similar to that of the kappa opioid receptor and , The other mechanisms that have been suggested to respectively78-80 , thus suggesting that these systems be involved in the renal responses of N/OFQ inclu- may evoke changes in renal excretory function via de the ADH and oxytocin. Anatomical studies have common pathways. Since the renal responses pro- demonstrated that the ORL-1 receptor mRNA and duced by central administration of N/OFQ were not the precursor N/OFQ mRNA are expressed in seve- blocked by pretreatment with the kappa opioid re- ral nuclei of the hypothalamus86,87. Therefore, the ceptor antagonist, nor-, it was sug- renal effects of N/OFQ may be caused by its effect gested that nociceptin produced a selective water di- on the secretion of ADH and/or oxytocin. However, uresis via a central nervous system mechanism inde- the role of hypothalamic ORL-1 receptors in renal pendent of kappa-opioid receptors. Together, these responses to N/OFQ should be further investigated. were the first observations suggesting that endoge- nous N/OFQ may be a novel peptide involved in In regard to future therapeutic importance, the non- the central control of water balance and electrolyte peptide analogues of nociceptin may offer the first concentration85. clinically useful therapeutic tools for the manage- ment of hyponatremia and water-retaining diseases The mechanisms by which N/OFQ alters renal exc- (such as patients with the syndrome of inappropri- retion of water and sodium are not still well unders- ate secretion of antiduretic hormone, congestive he- tood but it appears that a number of pathways art failure, cirrhosis with ascites, or in the adult res- might be important in mediating these responses piratory distress syndrome) since they cause diure- including renal nerves, vasopressin and oxytocin. sis and concurrent antinatriuresis. While kappa- As mentioned in previous sections, both the vascu- agonists (e.g. , spiradoline) have the po- lar and tubular segments of the kidneys are densely tential to be effective as water diuretics because of innervated with renal sympathetic nerves and the their diuretic and antinatriuretic effects, the CNS si- changes in renal nerve activity significantly alters de effects (e.g. dysphoria) limit their clinical use in the specific functions of the kidneys i.e. GFR, RBF, humans. renal blood flow, and tubular handling of water and sodium44. The increased activity of renal sympathe- 3. CONCLUSION tic nerves increases sodium and water reabsorption thus causing marked decrease in urinary sodium As discussed in previous sections, administration of and water excretion. It has been shown that central opioid receptor agonists is capable of producing administration of N/OFQ evoked a significant dec- changes in the renal excretion of water and sodium. rease in renal sympathetic nerve activity in parallel The particular renal excretory response (e.g. diuresis to antinatriuretic and diuretic responses. However, or antidiuresis) appears to depend, at least in part, renal nerves do not appear to mediate the renal ef- on the type of opioid receptor activated. However,

33 Sezen an important question that remains to be answered receptors, Nature 267, 495-499, 1977. is whether endogenous opioids participate in the 5. Mansour A, Fox CA, Akil H, and Watson SJ. Opioid- physiological regulation of renal function and main- receptor mRNA expression in the rat CNS: anatomical and functional implications, Trends Neurosci. 18, 22- tenance of daily sodium and/or water balance. This 29, 1995. possibility might be investigated by determining the 6. Wittert G, Hope P, and Pyle D. Tissue distribution of changes in renal excretory function produced by the opioid receptor gene expression in the rat, Biochem. administration of an opioid receptor antagonist. If Biophys. Res. Commun. 218, 877-881, 1996. endogenous opioid systems have a tonic influence 7. Reisine T. Receptors, Neuropharmacol. 34, 463- on the renal handling of water and/or sodium, then 472, 1995. administration would be expected 8. Olson GA, Olson RD, and Kastin AJ. Endogenous opi- ates, Peptides. 15, 1513-1556, 1994. to produce a change in renal excretory function. 9. Kapusta DR. Opioid mechanisms controlling renal Using this approach, however, controversial results function, Clin. Exp. Pharmacol. Physiol. 22, 891-902, regarding the effects of endogenous opioid systems 1995. on renal function have been observed, and in gene- 10. Kapusta DR, Jones SY, Kopp UC, and Di Bona GF. Ro- ral opioid systems appear to remain quiescent and le of renal nerves in excretory responses to exogenous have no influence on renal function until activated and endogenous opioid peptides, J. Pharmacol. Exp. by a particular condition or stimulus (e.g. dietary so- Ther. 248, 1039-1047, 1989. 11. Gutkowska J, Strick DM, Pan L, and McCann SM. Ef- dium restriction, stress)22,23,63. fects of morphine on urine output: possible role of at- rial natriuretic factor. Eur. J. Pharmacol. 242, 7-13, In conclusion, to elucidate how opioid systems af- 1993. fect kidney function, it is important to understand 12. Kapusta DR, and Dzialowski E. Central mu opioids how each opioid system acts individually, or in con- mediate differential control of urine flow rate and uri- cert, to modify the renal excretion of water and sodi- nary sodium excretion in conscious rats, Life Sci. 56, um. The knowledge of how opioid systems partici- PL243-248, 1995. 13. Kapusta DR, Jones SY, and Di Bona GF. Renal mu-opi- pate in the renal handling of water and sodium un- oid receptor mechanisms in regulation of renal functi- der physiologic or pathologic conditions will help on in rats, J. Pharmacol. Exp. Ther. 258, 111-117, 1991. the development of better therapeutics for clinical 14. Gutkowska J, and Schiller PW. Renal effects of TAPP, use. a highly selective µ-opioid agonist, Br. J. Pharmacol. 119, 239-244, 1996. ACKNOWLEDGEMENT 15. Genest J. Volume hormones and blood pressure, Ann. Int. Med. 98, 744-749, 1983. The research in author’s lab was supported by TÜB‹- 16. Di Bona GF. Neural mechanisms in body fluid home- ostasis, Fed. Proc. 45, 2871-2877, 1986. TAK SBAG-AYD 314 and Novartis Farmakoloji Dal› 17. Guyton A. Blood pressure control- special role of the Araflt›rma Destekleri-2000. kidneys and body fluids, Science 252, 1813-1816, 1991. 18. Roman RJ. Pressure diuresis mechanism in the control REFERENCES of renal function and arterial pressure, Fed. Proc. 45, 1. Pert CB, and Snyder SH. Opiate receptor: Demonstra- 2878-2884, 1986. tion in nervous tissue, Science 179, 1011-1014, 1973. 19. Brown J. Is α-ANP primarily a natriuretic hormone?, 2. Simon EJ, Hiller JM, and Edelman I. Stereospecific bin- Trends Pharmacol. Sci. 9, 312-313, 1988. ding of the potent [3H] to 20. Stellar E.: Salt apetite: its neuroendocrine basis, Acta rat-brain homogenate, Proc. Natl. Acad. Sci. USA 70, Neurobiol. Exp. 53, 475-484, 1993. 1947-1949, 1973. 21. Hays RM. Cellular and molecular events in the action 3. Terenius L. Stereospecific interaction between narcotic of antidiuretic hormone, Kidney Int. 49, 1700-1705, and a synaptic plasma membrane fraction 1996. of rat cerebral cortex. Acta Pharmacol. Toxicol. 32, 317- 22. Kapusta DR, Jones SY, and Di Bona GF. Opioids in the 320, 1973. systemic hemodynamic and renal responses to stress 4. Lord JH, Waterfield AA, Hughes J, and Kosterlitz HW. in conscious spontaneously hypertensive rats, Hyper- Endogenous opioid peptides: multiple agonists and tension. 13, 808-816, 1989.

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